Skip to content

Advertisement

Retrovirology

What do you think about BMC? Take part in

Open Access

Hematopoietic stem cells and retroviral infection

  • Prabal Banerjee1, 2,
  • Lindsey Crawford1,
  • Elizabeth Samuelson1 and
  • Gerold Feuer1, 2Email author
Contributed equally
Retrovirology20107:8

https://doi.org/10.1186/1742-4690-7-8

Received: 1 October 2009

Accepted: 4 February 2010

Published: 4 February 2010

Abstract

Retroviral induced malignancies serve as ideal models to help us better understand the molecular mechanisms associated with the initiation and progression of leukemogenesis. Numerous retroviruses including AEV, FLV, M-MuLV and HTLV-1 have the ability to infect hematopoietic stem and progenitor cells, resulting in the deregulation of normal hematopoiesis and the development of leukemia/lymphoma. Research over the last few decades has elucidated similarities between retroviral-induced leukemogenesis, initiated by deregulation of innate hematopoietic stem cell traits, and the cancer stem cell hypothesis. Ongoing research in some of these models may provide a better understanding of the processes of normal hematopoiesis and cancer stem cells. Research on retroviral induced leukemias and lymphomas may identify the molecular events which trigger the initial cellular transformation and subsequent maintenance of hematologic malignancies, including the generation of cancer stem cells. This review focuses on the role of retroviral infection in hematopoietic stem cells and the initiation, maintenance and progression of hematological malignancies.

Introduction

Hematopoiesis is a highly regulated and hierarchical process wherein hematopoietic stem cells (HSCs) differentiate into mature hematopoietic cells [1]. It is a process controlled by complex interactions between numerous genetic processes in blood cells and their environment. The fundamental processes of self-renewal and quiescence, proliferation and differentiation, and apoptosis are governed by these interactions within both hematopoietic stem cells and mature blood cell lineages. Under normal physiologic conditions, hematopoietic homeostasis is maintained by a delicate balance between processes such as self-renewal, proliferation and differentiation versus apoptosis or cell-cycle arrest in hematopoietic progenitor/hematopoietic stem cells (HP/HSCs). Under stress conditions, such as bleeding or infection, fewer HP/HSCs undergo apoptosis while increased levels of cytokines and growth factors enhance proliferation and differentiation. In a normally functioning hematopoietic system, the kinetics of hematopoiesis return to baseline levels when the stress conditions end. Deregulation of the signaling pathways that control the various hematopoietic processes leads to abnormal hematopoiesis and is associated with the development of cancer, including leukemia (reviewed in [2]).

Although not fully characterized, deregulation of normal hematopoietic signaling pathways in HP/HSCs following viral infection has previously been documented [35]. Previous studies demonstrated productive infection of HP/HSCs by retroviruses and suggested that retroviral mediated leukemogenesis shares similarities with the development of other types of cancer, including the putative existence of cancer stem cells (CSCs) [6, 7]. Here we discuss the evidence demonstrating that retroviruses can infect HP/HSCs, and we speculate on the ability of Human T-cell lymphotropic virus type 1 (HTLV-1) to generate an "infectious" leukemic/cancer stem cell (ILSC/ICSC).

What Defines a HSC?

HSCs are pluripotent stem cells that can generate all hemato-lymphoid cells. A cell must meet four basic functional requirements to be defined as a HSC: 1) the capability for self-renewal, 2) the capability to undergo apoptosis, 3) the maintenance of multilineage hematopoiesis, and 4) the mobilization out of the bone marrow into the circulating blood. The ability of HSCs to permanently reconstitute an irradiated recipient host is the most stringent test to evaluate if a population is a true HSC. Long-term transplantation experiments suggest a clonal diversity model of HSCs where the HSC compartment consists of a fixed number of different types of HSCs, each with an epigenetically preprogrammed fate. The HP/HSC population is typically defined by surface expression of CD34 and represents a heterogeneous cell population encompassing stem cells, early pluripotent progenitor cells, multipotent progenitor cells, and uncommitted differentiating cells [8]. HSCs have the potential to proliferate indefinitely and can differentiate into mature hematopoietic lineage specific cells.

In adults, HSCs are maintained within the bone marrow and differentiate to produce the requisite number of highly specialized cells of the hematopoietic system. HSCs differentiate into two distinctive types of hematopoietic progenitors: 1) a common lymphoid progenitor (CLP) population that generates B-cells, T-cells and NK cells, and 2) a common myeloid progenitor (CMP) population that generates granulocytes, neutrophils, eosinophils, macrophages and erythrocytes (Figure 1). Lineage commitment of these progenitors involves a complex process that can be induced in response to a variety of factors, including the modulation of hematopoietic-associated cytokines and transcription factors. These factors serve dual purposes both by maintaining pluripotency and by actively inducing lineage commitment and differentiation of HSCs [918]
Figure 1

Hematopoiesis and retroviral infection: CD34+ hematopoietic stem cells (HSCs) can undergo self-renewal as well as undergoing maturation to give rise to common lymphoid progenitor (CLP) and common myeloid progenitor (CMP) cells, which serve as precursors to all lymphoid and myeloid cells respectively. HSCs as well as other lineage specific progenitors are permissive for infection by a variety of murine and human retroviruses including HIV-1 and HTLV-1.

Leukemia Stem Cells/Cancer Stem Cells (LSC/CSC)

The cancer stem cell hypothesis postulates that cancer can be initiated, sustained and maintained by a small number of malignant cells that have HSC-like properties including self-renewal and pluripotency [1921]. The hierarchical organization of leukemia was first proposed by Fialkow et al. in the 1970s, and it was later demonstrated that acute myeloid leukemia (AML) contains a diversity of cells of various lineages but of monoclonal origin [22]. It is now well established that HSCs are not only responsible for the generation of the normal hematopoietic system but can also initiate and sustain the development of leukemia, including AML [2, 7, 23]. This hematopoietic progenitor, termed a leukemic/cancer stem cell (LSC/CSC), is the result of an accumulation of mutations in normal HSCs that affect proliferation, apoptosis, self-renewal and differentiation [24]. One of the most well established models for this theory came from the seminal work of John Dick and colleagues that established cancer stem cells at the top of a hierarchical pyramid for the establishment of AML [25]. Many signaling pathways, such as the Wnt signaling pathway, that have been classically associated with solid cancers are now also associated with HSC development and disease [26, 27]. CSCs have been unequivocally identified in AML and are also suspected to play a role in other leukemias, including chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) [2830].

In order to be defined as a LSC/CSC, cells must have the ability to generate the variety of differentiated leukemic cells present in the original tumor and must demonstrate self-renewal. The classical experiment to define a cancer stem cell is its ability to reproduce the disease phenotype of the original malignancy in immunocompromised mice. LSC/CSC have the ability to recapitulate the original disease phenotype following transplantation into NOD/SCID mice as illustrated by the transplantation of CD34+CD38- LSC/CSC obtained from AML patients [25, 31, 32]. Interestingly, the CD34+CD38- cell surface phenotype of LSC/CSC is shared by immature hematopoietic precursors including HSCs, raising the possibility that LSC/CSC arise from HSCs. Indeed, the transplantation of mature CD34+CD38+ cells fails to recapitulate AML in NOD/SCID mice indicating that the HSC rather than the more mature CD34+CD38+ progenitor cell, is the LSC/CSC. The identification and characterization of LSC/CSC is critical for designing specific therapies since LSC/CSCs are relatively resistant to traditional radiation and chemotherapy [3335]. This theory provides an attractive model for leukemogenesis because the self-renewal of HSCs allows for multiple genetic mutations to occur within their long life span. For HSCs to become LSC/CSC, fewer genetic mutations may be required than in mature hematopoietic cells, which must also acquire self-renewal capacity [36].

The Cancer Stem Cell Hypothesis

There are currently three hypotheses that address the question of which target cell in cancer undergoes leukemic transformation (Figure 2) [34]. The first hypothesis proposes that multiple cell types within the stem and progenitor cell hierarchy are susceptible to transformation. Mutational events alter normal differentiation patterns and promote clonal expansion of leukemic cells from a specific differentiation state. The second hypothesis proposes that the mutations responsible for transformation and progression to leukemia occur in primitive multipotent stem cells and result in the development of a LSC/CSC. Thus, disease heterogeneity results from the ability of the LSC/CSC to differentiate and acquire specific phenotypic lineage markers [37]. The final hypothesis proposes that progression to acute leukemia may require a series of genetic events beginning with clonal expansion of a transformed LSC/CSC. This "two-hit" model of leukemogenesis suggests that there is a pre-leukemic stem cell that has undergone an initial transformation event, but has not yet acquired the additional mutations necessary to progress to leukemia [38].
Figure 2

Generation of Leukemic Stem Cells. Three hypotheses have been proposed that lead to the development of leukemic stem cells (LSC/CSC): (A) LSC/CSC might arise from either a hematopoietic stem cell (HSC), hematopoietic progenitor cell (HPC), committed lymphoid progenitor (CLP) or committed myeloid progenitor (CMP), (B) from a multipotent HSC or HPC into LSC/CSC through a single transformation event or, (C) from HSC or HPCs through a series of transformation events initiated by the generation of a pre-LSC/CSC.

Deregulation of genes involved in normal HSC self-renewal and differentiation in human cancer suggests an overlap in the regulatory pathways used by normal and malignant stem cells. Emerging evidence suggests that both normal and cancer stem cells share common developmental pathways. Since the signaling pathways that normally regulate HSC self-renewal and differentiation are also associated with tumorigenesis, it has been proposed that HSCs can be the target for transformation in certain types of cancer [20]. HSCs already have the inherent ability for self-renewal and persist for long periods of time in comparison to the high turnover rate of mature, differentiated cells. HSCs possess two distinctive properties that can be deregulated to initiate and sustain neoplastic malignancies, namely self-renewal and proliferation. Retroviral infection in HSCs may therefore result in the accumulation of mutations and in the modulation of key hematopoiesis-associated gene expression patterns. The alteration of normal hematopoietic signaling pathways, including those related to self-renewal and differentiation, may lead to the generation of a LSC/CSC population. During normal hematopoiesis, the HSC undergoes self-renewal or enters a committed, lineage specific differentiation and maturation pathway. Once HSCs commit to a lineage specific pathway and become terminally differentiated, they lose the capacity to undergo self-renewal [39, 40]. LSC/CSC however can undergo long-term proliferation without entering terminal differentiation resulting in the manifestation of hematological malignancies.

Retroviral Infection and Hematopoiesis

Recent evidence suggests that viral infection may have a profound influence on normal hematopoiesis [41]. Viral infection of HP/HSCs may adversely affect the levels of cytokines and transcription factors vital for proliferation and differentiation. Alternatively, viral infection may induce cytolysis, apoptosis and/or the destruction of progenitor cells, resulting in perturbation of hematopoiesis. Additionally, infected HPCs may differentiate resulting in dissemination of pathogens into diverse anatomical sites and to an effective spread of infection.

HP/HSCs can also serve as targets for cellular transformation by specific viruses partly because of their innate ability for self-renewal. CD34+ HP/HSCs are susceptible to infection with a number of viruses including HIV-1, HTLV-1, Hepatitis C virus, JC virus, Parvovirus, Human Cytomegalovirus (HCMV), and the Human Herpesviruses (HHV): HHV-5, HHV-6, HHV-7, HHV-8 [35, 4252]. The concept that viruses can invade, infect and establish a latent infection in the bone marrow was first demonstrated in studies with HCMV. HCMV infects a variety of cell types, including hematopoietic and stromal cells of the bone marrow, endothelial cells, epithelial cells, fibroblasts, neuronal cells, and smooth muscle cells [3, 5357]. The bone marrow is a site of HCMV latency [5, 58], but the primary cellular reservoir harboring latent virus within the bone marrow is controversial. Latent viral genomes are detected in CD14+ monocytes and CD33+ myeloid precursor cells [59, 60]. However HCMV can also infect CD34+ hematopoietic progenitor populations, and viral DNA sequences can be detected in CD34+ cells from healthy seropositive individuals [45, 46, 58, 61], suggesting that a primitive cell population serves as a renewable primary cellular reservoir for latent HCMV. The finding that HCMV DNA sequences are present in CD34+ cells of seropositive individuals is consistent with the hypothesis that HCMV resides in a HPC which subsequently gives rise to multiple blood cell lineages. Recently, it has also been proposed that other viruses such as HTLV-1 and Kaposi's Sarcoma Herpesvirus (KSHV) can also infect CD34+ HP/HSCs and establish latent infection within the BM resident cells [52, 62].

Apart from the establishment of latent infection within the bone marrow (BM), suppression of hematopoiesis has been documented to occur following infection of HPCs with HCMV, HHV-5, HHV-6, HIV-1, and measles virus either as a result of direct infection of HPCs or by indirect mechanisms such as disruption of the cytokine milieu within the stem cell niche following infection of bone marrow stromal cells. Our laboratory has reported that HTLV-1 and KSHV infection of CD34+ HP/HSCs suppresses hematopoiesis in vitro and that viral infection can be disseminated into mature lymphoid cell lineages in vivo when monitored in humanized SCID mice (HU-SCID) [52, 63, 64]. HTLV-1 and KSHV are both associated with hematological malignancies and it is plausible that CSCs can be generated following infection of HP/HSCs with these viruses.

Multiple retroviruses establish latent infections in HP/HSCs resulting in perturbation of hematopoiesis and induction of viral pathogenesis [6569]. Retroviral infections of HSCs can have adverse effects including induction of cell-cycle arrest and increased susceptibility to apoptosis, both would manifest in the suppression of hematopoiesis. Additionally, mutations and transcriptional deregulation of specific hematopoiesis-associated genes can skew normal hematopoiesis toward specific lineages and have been demonstrated to occur following infection of HP/HSCs with HIV-1, HTLV-1 and Friend Leukemia virus (FLV) [64, 70, 71].

Hematopoiesis occurs in the bone marrow microenvironment, a complex system comprised of many cell types including stromal cells that produce cytokines, growth factors and adhesion molecules vital for the maintenance, differentiation and maturation of HP/HSCs [9, 11]. Apart from infection of HSCs, retroviruses such as HIV-1 and Moloney Murine leukemia virus (M-MuLV) have been shown to infect bone marrow stromal cells, compromising their ability to support hematopoiesis and resulting in multilineage hematopoietic failure [72, 73].

Retroviruses and Leukemogenesis: The "two-hit" Hypothesis

Studies of retroviral induced leukemia have proven very useful in understanding the multi-step processes associated with leukemogenesis. Moreover, these models have broadened our understanding of hematopoiesis and hematopoietic stem cell biology. Retroviral infection models such as FLV and M-MuLV, which induce leukemic states in mice, have emerged as powerful tools to study the molecular mechanisms associated with leukemogenesis and the generation of LSC/CSCs [7478]. The emerging concept from these murine models is that acute leukemia arises from cooperation between two distinctive mutagenic events; one interfering with differentiation and another conferring a proliferative advantage to HP/HSCs (Figure 2C) [79, 80]. Studies from Avian Erythroblastosis virus (AEV), FLV and M-MuLV-induced leukemia/lymphoma models demonstrate that leukemia/lymphoma development depends on: (1) a mutation that impairs differentiation and blocks maturation, (2) a mutation that promotes autonomous cell growth, and (3) that neither mutational event is able to induce acute leukemia by itself [68, 81]. Thus, these models provide direct evidence for the "two-hit model" of leukemogenesis as has been proposed for some LSC/CSC induced hematological malignancies, including AML [79]. This concept is perhaps best illustrated by AEV infection in birds, FLV and MuLV infection in mice and in HTLV-1 infection in humans (Figure 3).
Figure 3

The "Two-Hit" Model of Retrovirus-Induced Leukemogenesis. (A) HTLV-1 infection of CD34+ hematopoietic progenitor and stem cells (HP/HSCs) leads to the development of Adult T-cell leukemia/lymphoma (ATLL). (B) FLV infection of erythroid progenitors leads to erythroleukemia. (C) M-MuLV infection of pro-T cells leads to T-cell lymphoma. The dotted line indicates the separation between the early and late phase of infection.

During AEV infection, the oncogenic tyrosine kinase v-Erb-b, together with the aberrant nuclear transcription factor v-Erb-A are transduced. The mutated thyroid hormone receptor α, v-Erb-A, becomes unresponsive to the ligand and actively recruits tyrosine kinases. These kinases, such as stem-cell factor activated c-kit, cause arrest of erythroid differentiation at the BFU-E/CFU-E stage. Additionally, v-Erb-b encodes a mutated epidermal growth factor receptor that induces extensive erythroblast self-renewal [69, 82]. These two virally-induced events promote the abnormal proliferation of erythroid progenitors and lead to the development of leukemia.

Another relevant leukemogenesis model induced by retroviral infection of HPCs is acute erythroleukemia caused by the infection of mice with FLV [8385]. FLV has two distinct viral components, a replication-competent Friend Murine Leukemia virus (F-MuLV) and a replication defective pathogenic component known as the Friend Spleen Focus Forming virus (F-SFFV) [8587]. The pathogenic component of FLV (F-SFFV) can infect a variety of hematopoietic cells, though early erythroid progenitors are the primary target for infection [86, 88]. F-SFFV can alter the normal growth and differentiation profile of erythroid progenitor cells leading to leukemogenesis. The induction of multistage erythroleukemia by FLV is also a two stage process: a pre-leukemic stage known as "erythroid hyperplasia" and a leukemic phase referred to as "erythroid cell transformation" (Figure 3B). The pre-leukemic stage is characterized by the infection and random integration of F-SFFV virus into erythroid precursor cells, forming an infected stem cell population, followed by the expression of the viral envelope glycoprotein gp55 on the cell surface. gp55 subsequently binds to the cellular receptor of erythropoietin (Epo-R) and interacts with the sf-Stk tyrosine kinase signaling pathway leading to a constitutive activation signal for the proliferation of undifferentiated erythroid progenitor cells independent of erythropoietin [83, 89, 90]. Within the proliferating erythroid progenitor cell population are infected cells with randomly integrated virus in the sp-1 locus, which leads to the activation and overexpression of PU.1. Originally isolated by Moreau-Gachelin and co-workers as a gene targeted for recurrent insertions of SFFV, PU.1 has subsequently been shown to be involved in terminal myeloid differentiation, B and T-cell development, as well as maintenance of normal erythropoiesis and HSC development [91, 92]. The over-expression of PU.1 in erythroid precursor cells as a result of SFFV integration leads to a block in erythroid differentiation and, in conjunction with the inactivation of p53, clonal expansion of these leukemic cells in susceptible mice [71, 91]. Thus FLV-mediated erythroleukemia is associated with two distinctive phases, "the pre-leukemic phase" mediated by gp55 binding to Epo-R and the "leukemic phase" mediated by SFFV integration and the subsequent over-expression of PU.1. This demonstrates that both AEV and FLV infection follow the two-hit model of the cancer stem cell hypothesis.

M-MuLV is a non-acute retrovirus that typically induces a T-cell lymphoma after a latency period of 3-6 months [67]. The tumor cells typically have the phenotype of immature T-cells (CD4-/CD8- or CD4+/CD8+) although some tumors show a more mature surface phenotype (CD4+/CD8-or CD4-/CD8+) [72, 93]. This led to the hypothesis that the virus might originally infect an immature T-cell or a HPC to form a ICSC/ILSC which then continues to differentiate post-infection, initially in the bone marrow and then in the thymus [67, 94]. Because T-lymphocytes develop in the thymus from bone marrow-derived immature precursors (pro-thymocytes), it has been proposed by several investigators that a bone marrow-thymus axis plays an important role in the development of T-cell lymphoma by M-MuLV [93, 9597]. Although the identity of the initial target cell for M-MuLV infection is still unknown, a two-stage leukemogenesis model for the development of M-MuLV-induced leukemia has been proposed [67]. In this model the animal is infected with MuLV on two separate occasions; the first infection occurs in the bone marrow at the pre-leukemic (early) phase which leads to hyperplasia and migration of infected lymphoid progenitors into the thymus where a subsequent infection leads to insertional activation of proto-oncogenes and outgrowth of the tumor resulting in the leukemic (late) phase of infection (Figure 3C). Early infection of the bone marrow is thought to be essential for establishment of the pre-leukemic state and for development of spleen hyperplasia. The late phase splenic hyperplasia is the result of a compensatory hematopoiesis due to diminished normal hematopoiesis in the bone marrow resulting from the establishment of the preleukemic phase and plays an integral role in the establishment of malignancy [98100].

Bovine leukemia virus (BLV) is a deltaretrovirus which causes leukemia/lymphoma in cattle [101] (reviewed by [102, 103]) and has been used as a model of HTLV-1 infection and disease. While B-cells are the primary target of BLV infection in contrast to the T-cell tropism displayed by HTLV-1, BLV-infected B lymphocytes are similarly arrested in G0/G1 and protected from apoptosis similar to properties demonstrated following HTLV-1 infection HP/HSCs [64, 104]. It has been suggested that CD5+ B-cell progenitors are more susceptible to BLV infection [105] and that there is a relationship between the B-cell phenotype and BLV tropism [106]. More recently, the existence of a pre-malignant clone has been proposed. This infected progenitor is detectable early after viral infection and could contribute to both genetic instability and clonal expansion, both characteristics of cancer cells [107]. It can therefore be speculated that the infection of progenitor populations by BLV may result in the establishment of an ILSC/ICSC and subsequent development of leukemia.

Much of the current knowledge about leukemic mechanisms originates with studies on AML. AML is characterized by the uncontrolled self-renewal of hematopoietic progenitors that fail to differentiate normally. Induction of AML is associated with a variety of mutations that can be broadly classified into two distinctive categories; mutations in genes encoding transcription factors involved with hematopoietic regulation and mutations in genes encoding proteins linked to survival and proliferation signaling pathways [7478, 108, 109]. Studies in mice have shown that neither type of mutation alone is sufficient for the induction of AML and that cooperative mutagenic events are required for disease initiation [69, 79]. The leukemogenesis models of AEV, FLV and MuLV validate this concept and underline the importance of these models for the study of down-stream molecular events associated with these mutagenic events. The emergence of LSC/CSC as a result of these oncogenic events would explain the complexity associated with hematological malignancy development such as AML and CML in humans.

Human T-cell Leukemia Virus Type-1 (HTLV-1) and Adult T-cell Leukemia/Lymphoma (ATLL)

Human T-cell leukemia/lymphoma virus type-1 (HTLV-1) is the causative agent of Adult T-cell Leukemia/Lymphoma (ATLL), an aggressive CD4+ leukemia/lymphoma [110]. ATLL is a rare T-cell malignancy characterized by hypercalcemia, hepatomegaly, splenomegaly, lymphadenopathy, the presence of a monoclonal expansion of malignant CD4+CD25+ T-cells that evolve from a polyclonal population of HTLV-1 infected CD4+ T-cells, and infiltration of lymphocytes into the skin and liver. HTLV-1 causes ATLL in a small percentage of infected individuals after a prolonged latency period of up to 20-40 years [111]. Although HTLV-1 can replicate by reverse transcription during the initial phase of infection, the integrated provirus is effectively replicated during proliferation of infected cells [112]. Typically, HTLV-1 infected cells can persist for decades in patients, and the infected cell population transits from a polyclonal phase into a monoclonal expansion during development and progression to ATLL.

There are four ATLL subtypes; acute, lymphomatous, chronic, and smoldering. The first two subtypes are associated with a rapidly progressing clinical course with a mean survival time of 5-6 months. Smoldering and chronic ATLL have a more indolent course and may represent transitional states towards acute ATLL. Clinical features of ATLL include leukemic cells with multi-lobulated nuclei called 'flower cells' which infiltrate into various tissues including the skin and the liver, abnormally high blood calcium levels, and concurrent opportunistic infections in patients [113, 114].

Although considerable progress has been made in understanding ATLL biology, the exact sequence of events occurring during the initial stages of malignancy, including the types of cells infected with HTLV-1, remain unclear. The primary target cells for HTLV-1 infection may not only influence HTLV-1 pathogenesis, but the sequestration of these cells in anatomical sites such as the bone marrow may also allow the virus to effectively evade the primary immune response against infection.

The Role of HSCs in HTLV-1 Infection and Pathogenesis

It has been previously reported by our laboratory and other investigators that HTLV-1 can infect human HP/HSCs [65, 115]. It has been hypothesized that HTLV-1 can specifically induce a latent infection in CD34+ HP/HSCs and can initiate preleukemic events in these progenitor cells [62]. These cells could potentially provide a durable reservoir for latent virus in infected individuals. It has been speculated that HTLV-1 infection of CD34+ HPCs may result in the generation of an ILSC/ICSC and may also induce perturbation of normal hematopoiesis, ultimately resulting in the outgrowth of malignant clones and the development of ATLL.

The development of ATLL correlates with neonatal or perinatal transmission of HTLV-1. HTLV-1 carries no cellular proto-oncogenes, and the oncogenic potential of the virus is linked to Tax1, a 40 kDa protein that functions as a trans-activator of viral gene expression and as a key component of HTLV-1-mediated transformation [116, 117]. Tax1 is a relatively promiscuous transactivator of both viral and cellular gene transcription and has been closely linked to the initiation of leukemogenesis. Apart from regulating viral gene expression through the 5' long terminal repeat (LTR), Tax1 can modulate the expression of a large variety of cellular genes and proteins including those encoding cytokines, apoptosis inhibitors, cell cycle regulators, transcription factors, and intracellular signaling molecules [116, 118120]. Tax1 usually induces cellular gene expression by the activation of transcription factors such as NF-κB and cyclic AMP response element-binding protein/activating transcription factor (CREB/ATF) [121]. Tax1 has also been shown to trans-repress transcription of certain cellular genes, including bax [122], human β-polymerase [119], cyclin A [123], lck [124], MyoD [125], INK4 [126], and p53 [127].

Transgenic mouse models of Tax1 expression have resulted in the generation of murine malignancies, including a mature T-cell malignancy, underlying the critical role of Tax1 in the manifestation of T-cell leukemia [128, 129]. Transgenic mice constructed to target expression of Tax1 to both immature and mature thymocytes using a Lck (Leukocyte-specific protein tyrosine kinase) promoter reproducibly develop immature and mature T-cell leukemia/lymphomas with immunological and pathological similarities to human ATLL [128, 129]. In a recent study by Yamazaki et al., splenic lymphomatous cells were harvested and purified from Tax-transgenic mice using a combination of immunological and physiological markers for CSCs and were injected into NOD/SCID mice using a limiting-dilution assay [6]. Injection with as few as 1 × 102 CSCs was sufficient to recapitulate the original lymphoma and reestablish CSCs in recipient NOD/SCID mice implicating a role for LSC/CSC in the establishment of ATLL.

LSC/CSCs have the ability to self-renew, are sequestered in the bone marrow microenvironment and are relatively resistant to conventional chemotherapeutic treatment regimens. The recent focus and characterization of the role of LSC/CSC in the induction of AML has generated a paradigm for LSC/CSC-generated cancers and has resulted in a re-evaluation of therapeutic strategies for successful targeting and elimination of leukemic cells in patients [31]. Although the Tax-transgenic mouse model is not a complete representation of ATLL manifestation in humans, this finding is intriguing particularly since other investigators have suggested that HTLV-1 infection in the human bone marrow and in human HP/HSCs specifically, may facilitate the early events initiating ATLL development [62]. Since a limited number of ATLL cases display phenotypes indicative of immature hematopoietic cells, HTLV-1 infection and transformation of HP/HSCs in humans may result in the generation of virally-infected ATLL LSC/CSC [130]. Lymphoma cells and LSC/CSC from Tax-transgenic mice were also demonstrated to sequester in the osteoblastic and vascular niches of the bone marrow in transplanted NOD/SCID mice. It is interesting to speculate that if ATLL arises from a LSC/CSC, then the sequestration of HTLV-1-infected HP/HSCs in the bone marrow microenvironment may be a contributing factor in the resistance of this leukemia to treatment with conventional chemotherapies. It remains to be determined if the recent results from the Tax-transgenic model are truly illustrative of the human disease. However, the Tax-transgenic murine model does provide several interesting clues into the mechanisms of HTLV-1 pathogenesis, and this may eventually group ATLL along with other hematological malignancies that have a LSC/CSC origin.

Recapitulating ATLL in 'humanized' SCID (HU-SCID) mice has been challenging, and previous attempts to directly infect mature human T-cells in the human thymus-liver conjoint organ in HU-SCID mice with HTLV-1 failed to induce a malignancy [65]. Recent data from our laboratory demonstrates that ex vivo infection of CD34+ HP/HSCs with HTLV-1 reproducibly and consistently results in development of a CD4+ T-cell lymphoma in HU-SCID mice [131]. Clearly, HTLV-1 infection of HP/HSCs plays a pivotal role in the initiation and accelerated progression of malignancy during the course of HTLV-1 pathogenesis.

HTLV-1 Infected CD34+HP/HSCs: Notch, PU.1 and micro-RNA Deregulation

Manifestation of ATLL in patients generally occurs decades after infection, suggesting that HTLV-1 latently infects bone marrow stem cells that are sequestered from immunological surveillance. It is conceivable that the initiation of leukemogenesis in HSCs involves the generation of a CSC/LSC that will eventually manifest into the monoclonal ATLL malignancy. Several pathways that regulate HSC self-renewal are also associated with human cancers, including hematopoietic malignancies such as T-cell leukemia [132] and T-ALL [133, 134]. It has previously been shown that disruption of normal HSC self-renewal signaling pathways can induce hematopoietic neoplasms [132, 135]. Two main reasons suggest that HSCs can serve as target cells for virally-induced leukemia/lymphoma. First, stem cells have constitutively activated self-renewal pathways, requiring maintenance of activation in contrast to the de novo activation required in a more differentiated cell. Second, self-renewal provides a persistent target for repeated viral infection and/or continual replication of integrated proviral DNA. HTLV-1 infection of CD34+ HP/HSCs deregulates normal HSC self-renewal pathways through a variety of potential mechanisms suggesting that HTLV-1 infection may generate ILSC/ICSC.

The Notch signaling pathway regulates self-renewal and differentiation of HSCs and has been implicated as a key regulator of human T and B-cell derived lymphomas [135, 136]. Studies using adult bone marrow transplantation into NOD/SCID mice demonstrate that inactivation of Notch1 arrests T-cell development at the earliest precursor stage [134] and promotes B-cell development in the thymus [137]. The modulation of Notch levels in LSC/CSC derived from Tax-transgenic mice suggests that Notch may contribute in the development of ATLL similar to its role in other T-cell malignancies such as T-ALL [133, 134].

The sp1 gene encodes for the transcription factor PU.1, which is a member of the ets family of transcription factors, is expressed at various levels in all hematopoietic cells. PU.1 expression has been shown to play an important role in the regulation of hematopoiesis [138, 139]. Specifically, expression of PU.1 is tightly controlled in HSCs and regulates the fate of cells differentiating into lymphocyte, macrophage or granulocyte lineages [140, 141]. Deregulation of PU.1 expression has been linked to the development of hematopoietic malignancies including the transformation of myeloid cells [92]. During hematopoiesis, PU.1 is required for hematopoietic development along both the lymphoid and myeloid lineages, but is down-regulated during erythropoiesis. In AML patients, mutations in Flt3 decrease PU.1 expression and block differentiation [141] while mutations in PU.1 impair development within both myeloid and lymphoid lineages [142]. Knockout mouse studies have shown that perturbation of PU.1 expression results not only in the loss of B-cells and macrophage development, but also delays T lymphopoiesis [143, 144]. Additionally, PU.1 supports the self-renewal of HSCs by regulating the multilineage commitment of multipotent progenitors, thereby maintaining a pool of pluripotent HSCs within the bone marrow [145, 146].

Notably the reduction in PU.1 expression in bone marrow derived CD34+ HP/HSCs has been shown to induce an intermediate stage of poorly differentiated pre-leukemic cells which, with the accumulation of additional genetic mutations, results in an aggressive form of AML [147]. The HTLV-I accessory protein p30 has also been shown to interact with the ets domain of PU.1 resulting in impairment of the DNA binding activity of PU.1 and subsequent inhibition of PU.1-dependent transcription [148]. HTLV-1 p30-mediated alteration of PU.1 expression may be a contributing factor in the deregulation of hematopoiesis due to HTLV-1 infection of HSCs and may contribute to the establishment of ILSC/ICSC.

Bmi-1 (B-lymphoma Mo-MuLV insertion region), which belongs to the polycomb group of epigenetic chromatin modifiers, was originally identified as an oncogene [149]. Bmi-1 is required for the maintenance of HSC self-renewal in mice and is also involved in regulation of genes controlling cell proliferation, survival and differentiation of HSCs [149152]. Deficiency of Bmi-1 results in a progressive loss of HSCs and in defects in the stem cell compartment of the nervous system [153]. Bmi-1 expression is elevated in HP/HSCs in contrast to differentiated hematopoietic cells, and both self-renewal as well as the in vivo repopulation potential of HSCs is dependent on Bmi-1 [152, 154156]. It has been reported that Bmi-1 is required for the activation and survival of pre-T-cells and during transition from DN to DP T-cells [157]. Bmi-1 is required for the proliferation of LSC/CSCs, and the deregulation of Bmi-1 is linked to human cancers [155, 158]. Notably LSC/CSCs from Tax1-transgenic mice show a robust down-regulation of Bmi-1, providing a mechanistic link between HTLV-1 infection and deregulation of hematopoiesis.

Micro-RNAs (miRNAs) are a class of non-coding RNAs, 20-25 nucleotides long, that play an important role in both normal and malignant hematopoiesis, including self-renewal, differentiation and lineage specificity of HPCs [159163] (reviewed in [164]). Loss of miRNAs has also been reported in a variety of cancers indicating that alteration of miRNA levels might play a critical role in tumorigenesis [165167]. miR-150 is preferentially expressed in the megakaryocytic lineage and has been recently shown to drive the differentiation of megakaryocyte-erythrocyte precursors toward megakaryocyte development at the expense of erythroid differentiation [168]. Over-expression of miR-221 and miR-222 interferes with the kit receptor and blocks engraftment of HSCs in humanized mice [169]. Over-expression of miRNA-181a has been linked to the development of AML and CLL [170, 171]. These studies highlight the role of miRNA in regulating normal hematopoiesis and suggest that miRNA expression may modulate the manifestation of hematopoietic malignancies.

Retroviruses such as HIV-1 and HTLV-1 have been recently shown to target miRNAs for modulation of key cellular pathways including cell-cycle regulation and immune responses [172174]. Specifically, miRNAs that are involved in the regulation of cell proliferation, apoptosis and immune responses are up-regulated in ATL cells [175, 176]. Bellon et al. recently demonstrated that miRNAs involved in normal hematopoiesis and immune responses are also profoundly deregulated in ATLL cells indicating a possible link between modulation of cellular miRNA expression and deregulation of hematopoiesis by HTLV-1 [177]. Specifically, significant changes in the expression of miR-223 and miR-150 in ATLL patient samples were identified. miR-223 controls the terminal differentiation pathway of HSCs and is upregulated following differentiation into myeloid and lymphoid progenitors [162]. The differential expression of miR-150 regulates lineage decision between T and B-cells. Ectopic expression of miR-150 in lymphoid progenitors enhances T lymphopoiesis with respect to B lymphopoiesis [178]. The deregulation of cellular miRNAs might contribute to the transformation process resulting in the development of ATLL.

HTLV-1 infection in HP/HSC could result in aberrant miRNA expression ultimately predisposing HSC development toward T lymphopoiesis. Since expression of these miRNAs (223 and 150) are restricted to HP/HSCs, CLPs and CMPs, patient derived primary ATLL cells may originated from an infected HPC population in contrast to in vitro-established HTLV-1 infected CD4+ T cell lines. This supports the hypothesis that ATLL cells are derived from HTLV-1 infected CD34+ HP/HSCs rather than virally transformed mature T-cells [64, 128, 129]. Upon differentiation of an HTLV-1 infected CD34+ HPC, the alteration of miRNA levels may favor T-cell differentiation, as recently demonstrated by the exclusive development of CD4+ mature T-cell lymphomas in HU-SCID mice reconstituted with CD34+ HPCs infected ex vivo with HTLV-1[131].

Tax1 and Cell Cycle Regulation in HP/HSCs

HTLV-1 Tax1 has been shown to induce G0/G1 cell cycle arrest leading to quiescence in both cultured mammalian cell lines and primary human CD34+ HPCs [116, 179, 180]. Likewise, the expression of Tax1 in Saccharomyces cerevisiae leads to growth arrest and loss of cell viability [181, 182]. Intriguingly, in addition to increasing the levels of cyclins and CDKs, Tax1 also increases the levels of CDK inhibitors p16Ink4, p21cip1/waf1 (p21) and p27kip (p27) in infected cells [63, 64, 179, 183, 184]. Over-expression of p21 inhibits two critical checkpoints in the mammalian cell cycle, namely G1/S and S/G2, through p53-independent and dependent pathways [185]. Moreover, p21 and p27 are the key contributors in the cell-cycle regulation of CD34+ HPCs [186188]. Tax1 has also been shown to suppress human mitotic checkpoint protein MAD1 resulting in deregulation of the G2/M phase of the cell cycle resulting in aneuploidy [189]

Cell cycle progression is highly regulated in CD34+ HPCs with a majority of CD34+ HPCs residing in quiescence and demonstrating a unique expression pattern of CDKs, cyclins, and CDK inhibitors. The CDK inhibitors p21 and p27, in particular, have been shown to be key contributors in restricting cell cycle entry from G0 and maintaining quiescence in CD34+ HPCs [186188]. We have previously shown that during HTLV-1 infection, induction of G0/G1 cell cycle arrest and suppression of multilineage hematopoiesis in HPCs is attributed to the concomitant activation of p21 and p27 in these cells by Tax1 [63, 64, 180]. Although Tax1 usually induces cellular gene expression by activation of transcription factors such as NF-κB, CREB/ATF and Akt [190], it has recently been suggested that Tax1 deregulation of p21 and p27 may also be mediated independently of NF-κB activation [191] and p53 [184]. Moreover, the reported absence of NF-κB activity in CD34+CD38- HSCs [192] suggests that HP/HSCs provide a unique microenvironment for HTLV-1 infection which stands in stark contrast to the cellular environment provided by mature CD4+ T lymphocytes. It may be inferred that Tax1-mediated cell cycle deregulation is cell-type specific, inducing cell cycle arrest in HPCs while concurrently maintaining the ability to activate cell proliferation in mature CD4+ T-lymphocytes.

Survivin, originally identified as a member of the inhibitor of apoptosis protein family, has recently been implicated in regulating hematopoiesis, cell cycle control and transformation [193196]. Survivin is expressed in normal adult bone marrow cells and in CD34+ HPCs where it regulates proliferation and/or survival, and survivin expression is upregulated by hematopoietic growth factors [197]. Notably, survivin has been shown to be a key mediator of early cell cycle entry in CD34+ HPCs and regulates progenitor cell proliferation through p21-dependent and independent pathways [198], in addition to regulating apoptosis of HSCs [199]. This implicates survivin as an integral cellular factor, regulating multiple aspects of hematopoiesis. HTLV-1 mediated suppression of hematopoiesis in CD34+ HPCs is regulated, in part, by down-regulation of survivin expression in these cells by Tax1 [64]. Notably, CD34+CD38- HSCs demonstrate elevated sensitivity to cell-cycle arrest following HTLV-1 infection in comparison to more mature CD34+CD38+ HPCs, suggesting that HTLV-1 may target stem cells to facilitate a latent infection in vivo by inducing cell cycle arrest to induce cellular quiescence (Figure 4).
Figure 4

The Role of HTLV-1 Infection of HSCs: Potential Mechanisms for Generation of an Infectious Leukemic Stem Cell (ILSC/ICSC). HTLV-1 infection and subsequent Tax1 expression can lead to either cell cycle arrest or generation of pre-leukemic stem cells (pre-LSC/CSC) from infected CD34+ hematopoietic progenitor and stem cells (HP/HSCs).

HTLV-1 Interaction with CD34+HP/HSCs: Emerging Views

Emerging evidence has led to a new view of HTLV-1 mediated leukemogenesis that correlates neonatal transmission of HTLV-1 with viral infection targeting of HP/HSCs and immature human thymocytes [63, 65, 115]. This hypothesis challenges the current view that mature differentiated CD4+ T-cells are the exclusive target for HTLV-1 infection and for the initiation of ATLL. Analysis of bone marrow samples from pediatric HTLV-1 infections would confirm the hypothesis that HTLV-1 infection enters and is sequestered in the CD34+HP/HSCs in the bone marrow. It is noteworthy that previous reports have demonstrated HTLV-1 transmission following a bone marrow transplantation procedure from a HTLV-1 infected donor [200]. HTLV-1 infection of HP/HSCs can result in skewing of hematopoiesis toward distinct cellular lineages and outgrowth of malignant clones leading to ATLL. HP/HSCs may be critical target cell for HTLV-1 infection and for establishment of latency in vivo providing a reservoir of infected cells which progresses, after the accumulation of additional molecular events, to the development of ATLL [62, 65]. This hypothesis is supported by recent identification of a rare CSC population in Tax-transgenic mice [6, 128]. Notably, our laboratory has detected a high incidence of HTLV-1 proviral sequences in CD34+ HP/HSCs from HTLV-1-infected patient peripheral blood lymphocyte samples, suggesting that HP/HSCs are a natural cellular reservoir for HTLV-1 infection [131]. The down-regulation of key hematopoietic genes, including Notch1 and Bmi-1, in CSCs from Tax-transgenic mice indicates that the CSC potentially emerges from primitive HPCs or immature thymocytes and highlights the role of Tax1 expression in the induction of lymphoproliferative disease (Figure 4). The role of HTLV-1 Tax in HP/HSCs includes cell cycle deregulation and perturbation of hematopoiesis, as we have previously reported [63, 180]. Clearly many parameters defining how HTLV-1 and its associated viral genes (including Tax1, p30 and HBZ [201]), may contribute to the development of a ILSC/ICSC in ATLL have yet to be established. The role of the HTLV-1 antisense encoded protein HBZ is of particular interest as it is consistently expressed in all ATLL patient cells examined in contrast to Tax1 which is usually silenced in ATLL cells [202, 203]. Emerging in vivo murine models, particularly the HU-SCID mouse models, will help characterize the pathobiology of HTLV-1 infection and establish the existence of ILSC/ICSC. Moreover, these models will allow for the identification of events resulting in leukemia-initiation and progression and for the pre-clinical therapeutic evaluation for this fatal malignancy which currently lacks effective treatment regimens.

Perspectives

Retroviral infection of HP/HSCs in the bone marrow clearly provides a reservoir for infected cells and results in dramatically altered patterns of hematopoiesis. Determining and identifying whether retroviruses, such as HTLV-1, exploit this cellular trait to establish an ILSC would present a new paradigm in the pathobiology of HTLV-1 infection and would allow novel targeted treatments to be designed in order to intervene and treat retroviral mediated neoplasms.

Notes

Abbreviations

LSC/CSC: 

leukemic stem cell/cancer stem cell

HP/HSC: 

hematopoietic progenitor/stem cell

HTLV-1: 

human T cell lymphotropic virus type 1

ILSC/ICSC: 

infectious leukemic/cancer stem cell

CLP: 

common lymphoid progenitor

CMP: 

common myeloid progenitor

AML: 

acute myeloid leukemia

ALL: 

acute lymphoblastic leukemia

CML: 

chronic myelogenous leukemia

HU-SCID mouse: 

humanized severe combined immunodeficient mouse

HIV-1: 

human immunodeficiency virus type-1

FLV: 

Friend leukemia virus

M-MuLV: 

Moloney murine leukemia virus

AEV: 

Avian erythroblastosis virus

BLV: 

Bovine leukemia virus

ATLL: 

Adult T cell leukemia/lymphoma

CREB/ATF: 

cyclic AMP response element-binding protein/activating transcription factor

Bmi-1: 

B-lymphoma Mo-MuLV insertion region

DN: 

double negative

DP: 

double positive

miRNAs: 

micro-RNAs.

Declarations

Acknowledgements

This work was supported by grants from the US National Institutes of Health (CA124595) and by the Empire State Stem Cell Fund through New York State Department of Health Contract (NYSTEM #C023059 and #N08G-127) to G.F. Opinions expressed here are solely those of the author and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York.

Authors’ Affiliations

(1)
Department of Microbiology and Immunology, SUNY Upstate Medical University
(2)
Center for Humanized SCID Mice and Stem Cell Processing Laboratory, SUNY Upstate Medical University

References

  1. Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL: Biology of Hematopoietic Stem Cells and Progenitors: Implications for Clinical Application. Annual Review of Immunology. 2003, 21: 759-806. 10.1146/annurev.immunol.21.120601.141007.PubMedGoogle Scholar
  2. Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 2001, 414: 105-111. 10.1038/35102167.PubMedGoogle Scholar
  3. Maciejewski JP, Bruening EE, Donahue RE, Mocarski ES, Young NS, St Jeor SC: Infection of hematopoietic progenitor cells by human cytomegalovirus. Blood. 1992, 80: 170-178.PubMedGoogle Scholar
  4. Manchester M, Smith KA, Eto DS, Perkin HB, Torbett BE: Targeting and hematopoietic suppression of human CD34+ cells by measles virus. J Virol. 2002, 76: 6636-6642. 10.1128/JVI.76.13.6636-6642.2002.PubMed CentralPubMedGoogle Scholar
  5. Goodrum F, Jordan CT, Terhune SS, High K, Shenk T: Differential outcomes of human cytomegalovirus infection in primitive hematopoietic cell subpopulations. Blood. 2004, 104: 687-695. 10.1182/blood-2003-12-4344.PubMedGoogle Scholar
  6. Yamazaki J, Mizukami T, Takizawa K, Kuramitsu M, Momose H, Masumi A, Ami Y, Hasegawa H, Hall WW, Tsujimoto H, Hamaguchi I, Yamaguchi K: Identification of cancer stem cells in a Tax-transgenic (Tax-Tg) mouse model of adult T- cell leukemia/lymphoma (ATL). Blood. 2009, 114 (13): 2709-20.PubMedGoogle Scholar
  7. Jordan CT, Guzman ML, Noble M: Cancer Stem Cells. The New England Journal of Medicine. 2006, 355: 1253-1261. 10.1056/NEJMra061808.PubMedGoogle Scholar
  8. Huang S, Terstappen LW: Lymphoid and myeloid differentiation of single human CD34+, HLA-DR+, CD38- hematopoietic stem cells. Blood. 1994, 83: 1515-1526.PubMedGoogle Scholar
  9. Allen TD, Dexter TM: The essential cells of the hemopoietic microenvironment. Exp Hematol. 1984, 12: 517-521.PubMedGoogle Scholar
  10. Laiosa CV, Stadtfeld M, Graf T: Determinants of lymphoid-myeloid lineage diversification. Annu Rev Immunol. 2006, 24: 705-738. 10.1146/annurev.immunol.24.021605.090742.PubMedGoogle Scholar
  11. Ogawa M: Differentiation and proliferation of hematopoietic stem cells. Blood. 1993, 81: 2844-2853.PubMedGoogle Scholar
  12. Galy A, Travis M, Cen D, Chen B: Human T, B:natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity. 1995, 3: 459-473. 10.1016/1074-7613(95)90175-2.PubMedGoogle Scholar
  13. Ikawa T, Kawamoto H, Fujimoto S, Katsura Y: Commitment of common T/Natural killer (NK) progenitors to unipotent T and NK progenitors in the murine fetal thymus revealed by a single progenitor assay. J Exp Med. 1999, 190: 1617-1626. 10.1084/jem.190.11.1617.PubMed CentralPubMedGoogle Scholar
  14. Akashi K, Traver D, Miyamoto T, Weissman IL: A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000, 404: 193-197. 10.1038/35004599.PubMedGoogle Scholar
  15. Weissman IL, Shizuru JA: The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood. 2008, 112: 3543-3553. 10.1182/blood-2008-08-078220.PubMed CentralPubMedGoogle Scholar
  16. Metcalf D: The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989, 339: 27-30. 10.1038/339027a0.PubMedGoogle Scholar
  17. Chao MP, Seita J, Weissman IL: Establishment of a Normal Hematopoietic and Leukemia Stem Cell Hierarchy. Cold Spring Harb Symp Quant Biol. 2008Google Scholar
  18. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL: Physiological migration of hematopoietic stem and progenitor cells. Science. 2001, 294: 1933-1936. 10.1126/science.1064081.PubMedGoogle Scholar
  19. Sell S, Pierce GB: Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest. 1994, 70: 6-22.PubMedGoogle Scholar
  20. Sawyers CL, Denny CT, Witte ON: Leukemia and the disruption of normal hematopoiesis. Cell. 1991, 64: 337-350. 10.1016/0092-8674(91)90643-D.PubMedGoogle Scholar
  21. Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA: The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. Embo J. 2001, 20: 1897-1909. 10.1093/emboj/20.8.1897.PubMed CentralPubMedGoogle Scholar
  22. Fialkow PJ, Singer JW, Adamson JW, Vaidya K, Dow LW, Ochs J, Moohr JW: Acute nonlymphocytic leukemia: heterogeneity of stem cell origin. Blood. 1981, 57: 1068-1073.PubMedGoogle Scholar
  23. Wang JC, Dick JE: Cancer stem cells: lessons from leukemia. Trends Cell Biol. 2005, 15: 494-501. 10.1016/j.tcb.2005.07.004.PubMedGoogle Scholar
  24. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, Preudhomme C: Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008, 22: 915-931. 10.1038/leu.2008.19.PubMedGoogle Scholar
  25. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994, 367: 645-648. 10.1038/367645a0.PubMedGoogle Scholar
  26. Zhu AJ, Watt FM: beta-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. Development. 1999, 126: 2285-2298.PubMedGoogle Scholar
  27. Chan EF, Gat U, McNiff JM, Fuchs E: A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet. 1999, 21: 410-413. 10.1038/7747.PubMedGoogle Scholar
  28. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL: Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004, 351: 657-667. 10.1056/NEJMoa040258.PubMedGoogle Scholar
  29. Sirard C, Lapidot T, Vormoor J, Cashman JD, Doedens M, Murdoch B, Jamal N, Messner H, Addey L, Minden M, Laraya P, Keating A, Eaves A, Lansdorp PM, Eaves CJ, Dick JE: Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis. Blood. 1996, 87: 1539-1548.PubMedGoogle Scholar
  30. Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ: Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer. 2005, 5: 899-904. 10.1038/nrc1740.PubMedGoogle Scholar
  31. Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997, 3: 730-737. 10.1038/nm0797-730.PubMedGoogle Scholar
  32. Custer RP, Basma GC, Bosma MJ: Severe Combined Immunodeficiency (SCID) in the Mouse: Pathology, Reconstitution, Neoplasms. American Journal of Pathology. 1985, 120: 464-477.PubMed CentralPubMedGoogle Scholar
  33. Deshpande AJ, Buske C: Lymphoid Progenitors as Candidate Cancer Stem Cells in AML. Cell Cycle. 2007, 6: 543-545.PubMedGoogle Scholar
  34. Hope KJ, Jin L, Dick JE: Human Acute Myeloid Leukemia Stem Cells. Archives of Medical Research. 2003, 34: 507-514. 10.1016/j.arcmed.2003.08.007.PubMedGoogle Scholar
  35. Chan W-I, Huntly BJP: Leukemia Stem Cells in Acute Myeloid Leukemia. Seminars in Oncology. 2008, 35: 326-335. 10.1053/j.seminoncol.2008.04.003.PubMedGoogle Scholar
  36. Tan BT, Park CY, Ailles LE, Weissman IL: The cancer stem cell hypothesis: a work in progress. Lab Invest. 2006, 86: 1203-1207. 10.1038/labinvest.3700488.PubMedGoogle Scholar
  37. McCulloch EA: Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture, 1982). Blood. 1983, 62: 1-13.PubMedGoogle Scholar
  38. Kosmider O, Moreau-Gachelin F: From mice to human: the "two-hit model" of leukemogenesis. Cell Cycle. 2006, 5: 569-570. 10.4161/cc.5.6.2577.PubMedGoogle Scholar
  39. Keller G: Hematopoietic stem cells. Curr Opin Immunol. 1992, 4: 133-139. 10.1016/0952-7915(92)90002-V.PubMedGoogle Scholar
  40. Till JE, McCulloch EA: Hemopoietic stem cell differentiation. Biochim Biophys Acta. 1980, 605: 431-459.PubMedGoogle Scholar
  41. Kolb-Maurer A, Goebel W: Susceptibility of hematopoietic stem cells to pathogens: role in virus/bacteria tropism and pathogenesis. FEMS Microbiol Lett. 2003, 226: 203-207. 10.1016/S0378-1097(03)00643-8.PubMedGoogle Scholar
  42. Segovia JC, Guenechea G, Gallego JM, Almendral JM, Bueren JA: Parvovirus infection suppresses long-term repopulating hematopoietic stem cells. J Virol. 2003, 77: 8495-8503. 10.1128/JVI.77.15.8495-8503.2003.PubMed CentralPubMedGoogle Scholar
  43. Sansonno D, Lotesoriere C, Cornacchiulo V, Fanelli M, Gatti P, Iodice G, Racanelli V, Dammacco F: Hepatitis C virus infection involves CD34(+) hematopoietic progenitor cells in hepatitis C virus chronic carriers. Blood. 1998, 92: 3328-3337.PubMedGoogle Scholar
  44. Monaco MC, Atwood WJ, Gravell M, Tornatore CS, Major EO: JC virus infection of hematopoietic progenitor cells, primary B lymphocytes, and tonsillar stromal cells: implications for viral latency. J Virol. 1996, 70: 7004-7012.PubMed CentralPubMedGoogle Scholar
  45. Movassagh M, Gozlan J, Senechal B, Baillou C, Petit JC, Lemoine FM: Direct infection of CD34+ progenitor cells by human cytomegalovirus: evidence for inhibition of hematopoiesis and viral replication. Blood. 1996, 88: 1277-1283.PubMedGoogle Scholar
  46. Sindre H, Tjoonnfjord GE, Rollag H, Ranneberg-Nilsen T, Veiby OP, Beck S, Degre M, Hestdal K: Human cytomegalovirus suppression of and latency in early hematopoietic progenitor cells. Blood. 1996, 88: 4526-4533.PubMedGoogle Scholar
  47. Zhuravskaya T, Maciejewski JP, Netski DM, Bruening E, Mackintosh FR, St Jeor S: Spread of human cytomegalovirus (HCMV) after infection of human hematopoietic progenitor cells: model of HCMV latency. Blood. 1997, 90: 2482-2491.PubMedGoogle Scholar
  48. Khaiboullina SF, Maciejewski JP, Crapnell K, Spallone PA, Dean Stock A, Pari GS, Zanjani ED, Jeor SS: Human cytomegalovirus persists in myeloid progenitors and is passed to the myeloid progeny in a latent form. Br J Haematol. 2004, 126: 410-417. 10.1111/j.1365-2141.2004.05056.x.PubMedGoogle Scholar
  49. Isomura H, Yamada M, Yoshida M, Tanaka H, Kitamura T, Oda M, Nii S, Seino Y: Suppressive effects of human herpesvirus 6 on in vitro colony formation of hematopoietic progenitor cells. J Med Virol. 1997, 52: 406-412. 10.1002/(SICI)1096-9071(199708)52:4<406::AID-JMV11>3.0.CO;2-E.PubMedGoogle Scholar
  50. Isomura H, Yoshida M, Namba H, Fujiwara N, Ohuchi R, Uno F, Oda M, Seino Y, Yamada M: Suppressive effects of human herpesvirus-6 on thrombopoietin-inducible megakaryocytic colony formation in vitro. J Gen Virol. 2000, 81: 663-673.PubMedGoogle Scholar
  51. Mirandola P, Secchiero P, Pierpaoli S, Visani G, Zamai L, Vitale M, Capitani S, Zauli G: Blood. 2000, 96: 126-131.PubMedGoogle Scholar
  52. Wu W, Vieira J, Fiore N, Banerjee P, Sieburg M, Rochford R, Harrington W, Feuer G: KSHV/HHV-8 infection of human hematopoietic progenitor (CD34+) cells: persistence of infection during hematopoiesis in vitro and in vivo. Blood. 2006, 108: 141-151. 10.1182/blood-2005-04-1697.PubMed CentralPubMedGoogle Scholar
  53. Sinzger C, Grefte A, Plachter B, Gouw AS, The TH, Jahn G: Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues. J Gen Virol. 1995, 76 (Pt 4): 741-750. 10.1099/0022-1317-76-4-741.PubMedGoogle Scholar
  54. Soderberg C, Larsson S, Bergstedt-Lindqvist S, Moller E: Definition of a subset of human peripheral blood mononuclear cells that are permissive to human cytomegalovirus infection. J Virol. 1993, 67: 3166-3175.PubMed CentralPubMedGoogle Scholar
  55. Soderberg C, Larsson S, Bergstedt-Lindqvist S, Moller E: Identification of blood mononuclear cells permissive of cytomegalovirus infection in vitro. Transplant Proc. 1993, 25: 1416-1418.PubMedGoogle Scholar
  56. Schrier RD, Nelson JA, Oldstone MB: Detection of human cytomegalovirus in peripheral blood lymphocytes in a natural infection. Science. 1985, 230: 1048-1051. 10.1126/science.2997930.PubMedGoogle Scholar
  57. Maciejewski JP, St Jeor SC: Human cytomegalovirus infection of human hematopoietic progenitor cells. Leuk Lymphoma. 1999, 33: 1-13.PubMedGoogle Scholar
  58. Mendelson M, Monard S, Sissons P, Sinclair J: Detection of endogenous human cytomegalovirus in CD34+ bone marrow progenitors. J Gen Virol. 1996, 77 (Pt 12): 3099-3102. 10.1099/0022-1317-77-12-3099.PubMedGoogle Scholar
  59. Taylor-Wiedeman J, Sissons JG, Borysiewicz LK, Sinclair JH: Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991, 72 (Pt 9): 2059-2064. 10.1099/0022-1317-72-9-2059.PubMedGoogle Scholar
  60. Hahn G, Jores R, Mocarski ES: Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci USA. 1998, 95: 3937-3942. 10.1073/pnas.95.7.3937.PubMed CentralPubMedGoogle Scholar
  61. von Laer D, Meyer-Koenig U, Serr A, Finke J, Kanz L, Fauser AA, Neumann-Haefelin D, Brugger W, Hufert FT: Detection of cytomegalovirus DNA in CD34+ cells from blood and bone marrow. Blood. 1995, 86: 4086-4090.PubMedGoogle Scholar
  62. Grant C, Barmak K, Alefantis T, Yao J, Jacobson S, Wigdahl B: Human T cell leukemia virus type I and neurologic disease: events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation. J Cell Physiol. 2002, 190: 133-159. 10.1002/jcp.10053.PubMedGoogle Scholar
  63. Tripp A, Banerjee P, Sieburg M, Planelles V, Li F, Feuer G: Induction of cell cycle arrest by human T-cell lymphotropic virus type 1 Tax in hematopoietic progenitor (CD34+) cells: modulation of p21cip1/waf1 and p27kip1 expression. J Virol. 2005, 79: 14069-14078. 10.1128/JVI.79.22.14069-14078.2005.PubMed CentralPubMedGoogle Scholar
  64. Banerjee P, Sieburg M, Samuelson E, Feuer G: Human T-cell lymphotropic virus type 1 infection of CD34+ hematopoietic progenitor cells induces cell cycle arrest by modulation of p21(cip1/waf1) and survivin. Stem Cells. 2008, 26: 3047-3058. 10.1634/stemcells.2008-0353.PubMedGoogle Scholar
  65. Feuer G, Fraser JK, Zack JA, Lee F, Feuer R, Chen IS: Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo. J Virol. 1996, 70: 4038-4044.PubMed CentralPubMedGoogle Scholar
  66. Folks TM, Kessler SW, Orenstein JM, Justement JS, Jaffe ES, Fauci AS: Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988, 242: 919-922. 10.1126/science.2460922.PubMedGoogle Scholar
  67. Fan H: Leukemogenesis by Moloney murine leukemia virus: a multistep process. Trends Microbiol. 1997, 5: 74-82. 10.1016/S0966-842X(96)10076-7.PubMedGoogle Scholar
  68. Moreau-Gachelin F, Wendling F, Molina T, Denis N, Titeux M, Grimber G, Briand P, Vainchenker W, Tavitian A: Spi-1/PU.1 transgenic mice develop multistep erythroleukemias. Mol Cell Biol. 1996, 16: 2453-2463.PubMed CentralPubMedGoogle Scholar
  69. Beug H, Bauer A, Dolznig H, von Lindern M, Lobmayer L, Mellitzer G, Steinlein P, Wessely O, Mullner E: Avian erythropoiesis and erythroleukemia: towards understanding the role of the biomolecules involved. Biochim Biophys Acta. 1996, 1288: M35-47.PubMedGoogle Scholar
  70. Zauli G, Vitale M, Re MC, Furlini G, Zamai L, Falcieri E, Gibellini D, Visani G, Davis BR, Capitani S, et al: In vitro exposure to human immunodeficiency virus type 1 induces apoptotic cell death of the factor-dependent TF-1 hematopoietic cell line. Blood. 1994, 83: 167-175.PubMedGoogle Scholar
  71. Moreau-Gachelin F, Robert-Lezenes J, Wendling F, Tavitian A, Tambourin P: Integration of spleen focus-forming virus proviruses in Friend tumor cells. J Virol. 1985, 53: 292-295.PubMed CentralPubMedGoogle Scholar
  72. Brightman BK, Davis BR, Fan H: Preleukemic hematopoietic hyperplasia induced by Moloney murine leukemia virus is an indirect consequence of viral infection. J Virol. 1990, 64: 4582-4584.PubMed CentralPubMedGoogle Scholar
  73. Moses AV, Williams S, Heneveld ML, Strussenberg J, Rarick M, Loveless M, Bagby G, Nelson JA: Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. Blood. 1996, 87: 919-925.PubMedGoogle Scholar
  74. Speck NA, Gilliland DG: Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002, 2: 502-513. 10.1038/nrc840.PubMedGoogle Scholar
  75. Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002, 100: 1532-1542. 10.1182/blood-2002-02-0492.PubMedGoogle Scholar
  76. Tenen DG: Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer. 2003, 3: 89-101. 10.1038/nrc989.PubMedGoogle Scholar
  77. Reilly JT: Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis?. Br J Haematol. 2005, 128: 18-34. 10.1111/j.1365-2141.2004.05236.x.PubMedGoogle Scholar
  78. Rosenbauer F, Koschmieder S, Steidl U, Tenen DG: Effect of transcription-factor concentrations on leukemic stem cells. Blood. 2005, 106: 1519-1524. 10.1182/blood-2005-02-0717.PubMed CentralPubMedGoogle Scholar
  79. Gilliland DG: Hematologic malignancies. Curr Opin Hematol. 2001, 8: 189-191. 10.1097/00062752-200107000-00001.PubMedGoogle Scholar
  80. Moreau-Gachelin F: Lessons from models of murine erythroleukemia to acute myeloid leukemia (AML): proof-of-principle of co-operativity in AML. Haematologica. 2006, 91: 1644-1652.PubMedGoogle Scholar
  81. Rulli K, Lenz J, Levy LS: Disruption of hematopoiesis and thymopoiesis in the early premalignant stages of infection with SL3-3 murine leukemia virus. J Virol. 2002, 76: 2363-2374. 10.1128/jvi.76.5.2363-2374.2002.PubMed CentralPubMedGoogle Scholar
  82. Schroeder C, Gibson L, Nordstrom C, Beug H: The estrogen receptor cooperates with the TGF alpha receptor (c-erbB) in regulation of chicken erythroid progenitor self-renewal. Embo J. 1993, 12: 951-960.PubMed CentralPubMedGoogle Scholar
  83. Ruscetti SK: Erythroleukaemia induction by the Friend spleen focus-forming virus. Baillieres Clin Haematol. 1995, 8: 225-247. 10.1016/S0950-3536(05)80239-2.PubMedGoogle Scholar
  84. Moreau-Gachelin F: Multi-stage Friend murine erythroleukemia: molecular insights into oncogenic cooperation. Retrovirology. 2008, 5: 99-10.1186/1742-4690-5-99.PubMed CentralPubMedGoogle Scholar
  85. Friend C: Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia. J Exp Med. 1957, 105: 307-318. 10.1084/jem.105.4.307.PubMed CentralPubMedGoogle Scholar
  86. Tambourin P, Wendling F: Malignant transformation and erythroid differentiation by polycythaemia-inducing Friend virus. Nat New Biol. 1971, 234: 230-233. 10.1038/234230a0.PubMedGoogle Scholar
  87. Axelrad AA, Steeves RA: Assay for Friend Leukemia Virus: Rapid Quantitative Method Based on Enumeration of Macroscopic Spleen Foci in Mice. Virology. 1964, 24: 513-518. 10.1016/0042-6822(64)90199-0.PubMedGoogle Scholar
  88. Fredrickson T, Tambourin P, Wendling F, Jasmin C, Smajda F: Target cell of the polycythemia-inducing Friend virus: studies with myleran. J Natl Cancer Inst. 1975, 55: 443-446.PubMedGoogle Scholar
  89. Zon LI, Moreau JF, Koo JW, Mathey-Prevot B, D'Andrea AD: The erythropoietin receptor transmembrane region is necessary for activation by the Friend spleen focus-forming virus gp55 glycoprotein. Mol Cell Biol. 1992, 12: 2949-2957.PubMed CentralPubMedGoogle Scholar
  90. Li JP, Hu HO, Niu QT, Fang C: Cell surface activation of the erythropoietin receptor by Friend spleen focus-forming virus gp55. J Virol. 1995, 69: 1714-1719.PubMed CentralPubMedGoogle Scholar
  91. Moreau-Gachelin F, Tavitian A, Tambourin P: Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature. 1988, 331: 277-280. 10.1038/331277a0.PubMedGoogle Scholar
  92. Kastner P, Chan S: PU.1: a crucial and versatile player in hematopoiesis and leukemia. Int J Biochem Cell Biol. 2008, 40: 22-27. 10.1016/j.biocel.2007.01.026.PubMedGoogle Scholar
  93. Brightman BK, Chandy KG, Spencer RH, Gupta S, Pattengale PK, Fan H: Characterization of lymphoid tumors induced by a recombinant murine retrovirus carrying the avian v-myc oncogene. Identification of novel (B-lymphoid) tumors in the thymus. J Immunol. 1988, 141: 2844-2854.PubMedGoogle Scholar
  94. Lazo PA, Klein-Szanto AJ, Tsichlis PN: T-cell lymphoma lines derived from rat thymomas induced by Moloney murine leukemia virus: phenotypic diversity and its implications. J Virol. 1990, 64: 3948-3959.PubMed CentralPubMedGoogle Scholar
  95. Buckheit RW, Kurtzberg J, Bolognesi DP, Weinhold KJ: The coenrichment of stem cells, prothymocytes, and stromal elements with ecotropic retrovirus-producing cells from the bone marrow of leukemia-prone AKR mice. Virology. 1988, 162: 354-361. 10.1016/0042-6822(88)90475-8.PubMedGoogle Scholar
  96. Haran-Ghera N: Potential leukemic cells among bone marrow cells of young AKR/J mice. Proc Natl Acad Sci USA. 1980, 77: 2923-2926. 10.1073/pnas.77.5.2923.PubMed CentralPubMedGoogle Scholar
  97. Haran-Ghera N, Rubio N, Leef F, Goldstein G: Characteristics of preleukemia cells induced in mice. Cell Immunol. 1978, 37: 308-314. 10.1016/0008-8749(78)90199-5.PubMedGoogle Scholar
  98. Belli B, Fan H: The leukemogenic potential of an enhancer variant of Moloney murine leukemia virus varies with the route of inoculation. J Virol. 1994, 68: 6883-6889.PubMed CentralPubMedGoogle Scholar
  99. Fan H, Brightman BK, Belli B, Okimoto M, Tao M: Early (preleukemic) events in Moloney murine leukemia virus leukemogenesis. Leukemia. 1997, 11 (Suppl 3): 149-151.PubMedGoogle Scholar
  100. Li QX, Fan H: Combined infection by Moloney murine leukemia virus and a mink cell focus-forming virus recombinant induces cytopathic effects in fibroblasts or in long-term bone marrow cultures from preleukemic mice. J Virol. 1990, 64: 3701-3711.PubMed CentralPubMedGoogle Scholar
  101. Burny A, Bruck C, Cleuter Y, Couez D, Deschamps J, Ghysdael J, Gregoire D, Kettmann R, Mammerickx M, Marbaix G, et al: Bovine Leukemia Virus, a Versatile Agent with Various Pathogenic Effects in Various Animal Species. Cancer Research. 1985, 45: 4578s-4582.PubMedGoogle Scholar
  102. Gillet N, Florins A, Boxus M, Burteau C, Nigro A, Vandermeers F, Balon H, Bouzar A-B, Defoiche J, Burny A, Reichert M, Kettmann R, Willems L: Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human. Retrovirology. 2007, 4: 18-10.1186/1742-4690-4-18.PubMed CentralPubMedGoogle Scholar
  103. Gallo RC, Wong-Staal F: Retroviruses as Etiologic Agents of Some Animal and Human Leukemias and Lymphomas and as Tools for Elucidating the Molecular Mechanism of Leukemogenesis. Blood. 1982, 60: 545-555.PubMedGoogle Scholar
  104. Stone DM, Norton LK, Davis WC: Spontaneously proliferating lymphocytes from bovine leukaemia virus-infected, lymphocytic cattle are not the virus-expressing lymphocytes, as these cells are delayed in G0/G1 of the cell cycle and are spared from apoptosis. Journal of General Virology. 2000, 81: 971-981.PubMedGoogle Scholar
  105. Mirsky ML, Olmstead CA, Da Y, Lewin HA: The Prevalence of Proviral Bovine Leukemia Virus in Peripheral Blood Mononuclear Cells at Two Subclinical Stages of Infection. Journal of Virology. 1996, 70: 2178-2183.PubMed CentralPubMedGoogle Scholar
  106. Meirom R, Moss S, Brenner J: Bovine leukemia virus-gp51 antigen expression is associated with CD5 and IgM markers on infected lymphocytes. Veterinary Immunology and Immunopathology. 1997, 59: 113-119. 10.1016/S0165-2427(97)00056-1.PubMedGoogle Scholar
  107. Moules V, Pomier C, Sibon D, Gabet A-S, Reichert M: Fate of Premalignant Clones during the Asymptomatic Phase Preceeding Lymphoid Malignancy. Cancer Research. 2005, 65: 1234-1243. 10.1158/0008-5472.CAN-04-1834.PubMedGoogle Scholar
  108. Reilly JT: FLT3 and its role in the pathogenesis of acute myeloid leukaemia. Leuk Lymphoma. 2003, 44: 1-7. 10.1080/1042819021000040233.PubMedGoogle Scholar
  109. Michaud J, Scott HS, Escher R: AML1 interconnected pathways of leukemogenesis. Cancer Investigation. 2003, 21: 105-136. 10.1081/CNV-120018821.PubMedGoogle Scholar
  110. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC: Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980, 77: 7415-7419. 10.1073/pnas.77.12.7415.PubMed CentralPubMedGoogle Scholar
  111. Matsuoka M, Jeang KT: Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007, 7: 270-280. 10.1038/nrc2111.PubMedGoogle Scholar
  112. Mortreux F, Gabet AS, Wattel E: Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo. Leukemia. 2003, 17: 26-38. 10.1038/sj.leu.2402777.PubMedGoogle Scholar
  113. Matsuoka M: Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene. 2003, 22: 5131-5140. 10.1038/sj.onc.1206551.PubMedGoogle Scholar
  114. Takatsuki K: Discovery of adult T-cell leukemia. Retrovirology. 2005, 2: 16-10.1186/1742-4690-2-16.PubMed CentralPubMedGoogle Scholar
  115. Wencker M, Sausse C, Derse D, Gazzolo L, Duc Dodon M: Human T-cell leukemia virus type 1 Tax protein down-regulates pre-T-cell receptor alpha gene transcription in human immature thymocytes. J Virol. 2007, 81: 301-308. 10.1128/JVI.00766-06.PubMed CentralPubMedGoogle Scholar
  116. Boxus M, Twizere JC, Legros S, Dewulf JF, Kettmann R, Willems L: The HTLV-1 Tax interactome. Retrovirology. 2008, 5: 76-10.1186/1742-4690-5-76.PubMed CentralPubMedGoogle Scholar
  117. Jeang KT, Giam CZ, Majone F, Aboud M: Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J Biol Chem. 2004, 279: 31991-31994. 10.1074/jbc.R400009200.PubMedGoogle Scholar
  118. Sun SC, Ballard DW: Persistent activation of NF-kappaB by the tax transforming protein of HTLV-1: hijacking cellular IkappaB kinases. Oncogene. 1999, 18: 6948-6958. 10.1038/sj.onc.1203220.PubMedGoogle Scholar
  119. Jeang KT, Widen SG, Semmes OJt, Wilson SH: HTLV-I trans-activator protein, tax, is a trans-repressor of the human beta-polymerase gene. Science. 1990, 247: 1082-1084. 10.1126/science.2309119.PubMedGoogle Scholar
  120. Kasai T, Jeang KT: Two discrete events, human T-cell leukemia virus type I Tax oncoprotein expression and a separate stress stimulus, are required for induction of apoptosis in T-cells. Retrovirology. 2004, 1: 7-10.1186/1742-4690-1-7.PubMed CentralPubMedGoogle Scholar
  121. Yoshida M: Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol. 2001, 19: 475-496. 10.1146/annurev.immunol.19.1.475.PubMedGoogle Scholar
  122. Brauweiler A, Garrus JE, Reed JC, Nyborg JK: Repression of bax gene expression by the HTLV-1 Tax protein: implications for suppression of apoptosis in virally infected cells. Virology. 1997, 231: 135-140. 10.1006/viro.1997.8509.PubMedGoogle Scholar
  123. Kibler KV, Jeang KT: CREB/ATF-dependent repression of cyclin a by human T-cell leukemia virus type 1 Tax protein. J Virol. 2001, 75: 2161-2173. 10.1128/JVI.75.5.2161-2173.2001.PubMed CentralPubMedGoogle Scholar
  124. Lemasson I, Robert-Hebmann V, Hamaia S, Duc Dodon M, Gazzolo L, Devaux C: Transrepression of lck gene expression by human T-cell leukemia virus type 1-encoded p40tax. J Virol. 1997, 71: 1975-1983.PubMed CentralPubMedGoogle Scholar
  125. Riou P, Bex F, Gazzolo L: The human T cell leukemia/lymphotropic virus type 1 Tax protein represses MyoD-dependent transcription by inhibiting MyoD-binding to the KIX domain of p300. A potential mechanism for Tax-mediated repression of the transcriptional activity of basic helix-loop-helix factors. J Biol Chem. 2000, 275: 10551-10560. 10.1074/jbc.275.14.10551.PubMedGoogle Scholar
  126. Suzuki T, Narita T, Uchida-Toita M, Yoshida M: Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by tax protein of HTLV-1 through two distinct mechanisms. Virology. 1999, 259: 384-391. 10.1006/viro.1999.9760.PubMedGoogle Scholar
  127. Uittenbogaard MN, Giebler HA, Reisman D, Nyborg JK: Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein. J Biol Chem. 1995, 270: 28503-28506. 10.1074/jbc.270.48.28503.PubMedGoogle Scholar
  128. Hasegawa H, Sawa H, Lewis MJ, Orba Y, Sheehy N, Yamamoto Y, Ichinohe T, Tsunetsugu-Yokota Y, Katano H, Takahashi H, Matsuda J, Sata T, Kurata T, Nagashima K, Hall WW: Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med. 2006, 12: 466-472. 10.1038/nm1389.PubMedGoogle Scholar
  129. Ohsugi T, Kumasaka T, Okada S, Urano T: The Tax protein of HTLV-1 promotes oncogenesis in not only immature T cells but also mature T cells. Nat Med. 2007, 13: 527-528. 10.1038/nm0507-527.PubMedGoogle Scholar
  130. Yamada Y, Kamihira S, Amagasaki T, Kinoshita K, Kusano M, Chiyoda S, Yawo E, Ikeda S, Suzuyama J, Ichimaru M: Adult T cell leukemia with atypical surface phenotypes: clinical correlation. J Clin Oncol. 1985, 3: 782-788.PubMedGoogle Scholar
  131. Banerjee P, Tripp A, Lairmore M, Crawford L, Sieburg M, Ramos JC, Harrington WJ, Beilke MA, Feuer G: Adult T Cell Leukemia/Lymphoma Development in HTLV-1-Infected Humanized SCID Mice. Blood. 2010Google Scholar
  132. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J: TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991, 66: 649-661. 10.1016/0092-8674(91)90111-B.PubMedGoogle Scholar
  133. Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004, 306: 269-271. 10.1126/science.1102160.PubMedGoogle Scholar
  134. Radtke F, Wilson A, Mancini SJC, MacDonald HR: Notch regulation of lymphocyte development and function. Nat Immunol. 2004, 5: 247-253. 10.1038/ni1045.PubMedGoogle Scholar
  135. Jundt F, Schwarzer R, Dorken B: Notch signaling in leukemias and lymphomas. Curr Mol Med. 2008, 8: 51-59. 10.2174/156652408783565540.PubMedGoogle Scholar
  136. Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT: Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood. 2002, 99: 2369-2378. 10.1182/blood.V99.7.2369.PubMedGoogle Scholar
  137. Wilson A, MacDonald HR, Radtke F: Notch 1-deficient Common Lymphoid Precursors Adopt a B Cell Fate in the Thymus. J Exp Med. 2001, 194: 1003-1012. 10.1084/jem.194.7.1003.PubMed CentralPubMedGoogle Scholar
  138. Fisher RC, Scott EW: Role of PU.1 in hematopoiesis. Stem Cells. 1998, 16: 25-37. 10.1002/stem.160025.PubMedGoogle Scholar
  139. Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA: The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990, 61: 113-124. 10.1016/0092-8674(90)90219-5.PubMedGoogle Scholar
  140. Orkin SH: Diversification of Haematopoietic Stem Cells to Specific Lineages. Nature Reviews Genetics. 2000, 1: 57-64. 10.1038/35049577.PubMedGoogle Scholar
  141. Stirewalt DL: Fine-tuning PU.1. Nature Genetics. 2004, 36: 550-551. 10.1038/ng0604-550.PubMedGoogle Scholar
  142. Ikuta K, Uchida N, Friedman J, Weissman IL: Lymphocyte Development from Stem Cells. Annual Review of Immunology. 1992, 10: 759-783. 10.1146/annurev.iy.10.040192.003551.PubMedGoogle Scholar
  143. McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ, Maki RA: Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. Embo J. 1996, 15: 5647-5658.PubMed CentralPubMedGoogle Scholar
  144. Celada A, Borras FE, Soler C, Lloberas J, Klemsz M, van Beveren C, McKercher S, Maki RA: The transcription factor PU.1 is involved in macrophage proliferation. J Exp Med. 1996, 184: 61-69. 10.1084/jem.184.1.61.PubMedGoogle Scholar
  145. Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, Arinobu Y, Geary K, Zhang P, Dayaram T, Fenyus ML, Elf S, Chan S, Kastner P, Huettner CS, Murray R, Tenen DG, Akashi K: Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005, 106: 1590-1600. 10.1182/blood-2005-03-0860.PubMed CentralPubMedGoogle Scholar
  146. Dakic A, Metcalf D, Di Rago L, Mifsud S, Wu L, Nutt SL: PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J Exp Med. 2005, 201: 1487-1502. 10.1084/jem.20050075.PubMed CentralPubMedGoogle Scholar
  147. Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, Akashi K, Fiering S, Tenen DG: Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004, 36: 624-630. 10.1038/ng1361.PubMedGoogle Scholar
  148. Datta A, Sinha-Datta U, Dhillon NK, Buch S, Nicot C: The HTLV-I p30 interferes with TLR4 signaling and modulates the release of pro- and anti-inflammatory cytokines from human macrophages. J Biol Chem. 2006, 281: 23414-23424. 10.1074/jbc.M600684200.PubMedGoogle Scholar
  149. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M: Stem cells and cancer; the polycomb connection. Cell. 2004, 118: 409-418. 10.1016/j.cell.2004.08.005.PubMedGoogle Scholar
  150. Buszczak M, Spradling AC: Searching chromatin for stem cell identity. Cell. 2006, 125: 233-236. 10.1016/j.cell.2006.04.004.PubMedGoogle Scholar
  151. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM: Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 1991, 65: 753-763. 10.1016/0092-8674(91)90383-A.PubMedGoogle Scholar
  152. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF: Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003, 423: 302-305. 10.1038/nature01587.PubMedGoogle Scholar
  153. Lugt van der NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H, Valk van der M, Deschamps J, Sofroniew M, van Lohuizen M, et al: Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 1994, 8: 757-769. 10.1101/gad.8.7.757.PubMedGoogle Scholar
  154. Lessard J, Baban S, Sauvageau G: Stage-specific expression of polycomb group genes in human bone marrow cells. Blood. 1998, 91: 1216-1224.PubMedGoogle Scholar
  155. Lessard J, Sauvageau G: Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003, 423: 255-260. 10.1038/nature01572.PubMedGoogle Scholar
  156. Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, Ema H, Kamijo T, Katoh-Fukui Y, Koseki H, van Lohuizen M, Nakauchi H: Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004, 21: 843-851. 10.1016/j.immuni.2004.11.004.PubMedGoogle Scholar
  157. Miyazaki M, Miyazaki K, Itoi M, Katoh Y, Guo Y, Kanno R, Katoh-Fukui Y, Honda H, Amagai T, van Lohuizen M, Kawamoto H, Kanno M: Thymocyte proliferation induced by pre-T cell receptor signaling is maintained through polycomb gene product Bmi-1-mediated Cdkn2a repression. Immunity. 2008, 28: 231-245. 10.1016/j.immuni.2007.12.013.PubMedGoogle Scholar
  158. Raaphorst FM: Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors. Hum Mol Genet. 2005, 14 (Spec No 1): R93-R100. 10.1093/hmg/ddi111.PubMedGoogle Scholar
  159. Kluiver J, Kroesen BJ, Poppema S, Berg van den A: The role of microRNAs in normal hematopoiesis and hematopoietic malignancies. Leukemia. 2006, 20: 1931-1936. 10.1038/sj.leu.2404387.PubMedGoogle Scholar
  160. Garcia P, Frampton J: Hematopoietic lineage commitment: miRNAs add specificity to a widely expressed transcription factor. Dev Cell. 2008, 14: 815-816. 10.1016/j.devcel.2008.05.011.PubMedGoogle Scholar
  161. Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, Fabbri M, Coombes K, Alder H, Nakamura T, Flomenberg N, Marcucci G, Calin GA, Kornblau SM, Kantarjian H, Bloomfield CD, Andreeff M, Croce CM: MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood. 2008, 111: 3183-3189. 10.1182/blood-2007-07-098749.PubMed CentralPubMedGoogle Scholar
  162. Chen CZ, Li L, Lodish HF, Bartel DP: MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science. 2004, 303: 83-86. 10.1126/science.1091903.PubMedGoogle Scholar
  163. Chen CZ, Lodish HF: MicroRNAs as regulators of mammalian hematopoiesis. Semin Immunol. 2005, 17: 155-165. 10.1016/j.smim.2005.01.001.PubMedGoogle Scholar
  164. Gangaraju VK, Lin H: MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol. 2009, 10: 116-125. 10.1038/nrm2621.PubMed CentralPubMedGoogle Scholar
  165. Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 2006, 6: 857-866. 10.1038/nrc1997.PubMedGoogle Scholar
  166. Calin GA, Croce CM: MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006, 66: 7390-7394. 10.1158/0008-5472.CAN-06-0800.PubMedGoogle Scholar
  167. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Foa R, Martelli MF, Mecucci C, Croce CM, Falini B: Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci USA. 2008, 105: 3945-3950. 10.1073/pnas.0800135105.PubMed CentralPubMedGoogle Scholar
  168. Lu J, Guo S, Ebert BL, Zhang H, Peng X, Bosco J, Pretz J, Schlanger R, Wang JY, Mak RH, Dombkowski DM, Preffer FI, Scadden DT, Golub TR: MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell. 2008, 14: 843-853. 10.1016/j.devcel.2008.03.012.PubMed CentralPubMedGoogle Scholar
  169. Felli N, Fontana L, Pelosi E, Botta R, Bonci De, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C: MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proceedings of the National Academy of Sciences of the United States of America. 2005, 102: 18081-18086. 10.1073/pnas.0506216102.PubMed CentralPubMedGoogle Scholar
  170. Pallasch CP, Patz M, Park YJ, Hagist S, Eggle D, Claus R, Debey-Pascher S, Schulz A, Frenzel LP, Claasen J, Kutsch N, Krause G, Mayr C, Rosenwald A, Plass C, Schultze JL, Hallek M, Wendtner CM: miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia. Blood. 2009, 114 (15): 3255-64. 10.1182/blood-2009-06-229898.PubMed CentralPubMedGoogle Scholar
  171. Pons A, Nomdedeu B, Navarro A, Gaya A, Gel B, Diaz T, Valera S, Rozman M, Belkaid M, Montserrat E, Monzo M: Hematopoiesis-related microRNA expression in myelodysplastic syndromes. Leuk Lymphoma. 2009, 1-6. 10.1080/10428190903147645.Google Scholar
  172. Strebel K, Luban J, Jeang KT: Human cellular restriction factors that target HIV-1 replication. BMC Med. 2009, 7: 48-10.1186/1741-7015-7-48.PubMed CentralPubMedGoogle Scholar
  173. Bouzar AB, Willems L: How HTLV-1 may subvert miRNAs for persistence and transformation. Retrovirology. 2008, 5: 101-10.1186/1742-4690-5-101.PubMed CentralPubMedGoogle Scholar
  174. Ouellet DL, Plante I, Barat C, Tremblay MJ, Provost P: Emergence of a complex relationship between HIV-1 and the microRNA pathway. Methods Mol Biol. 2009, 487: 415-433. full_text.PubMed CentralPubMedGoogle Scholar
  175. Pichler K, Schneider G, Grassmann R: MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed T lymphocytes. Retrovirology. 2008, 5: 100-10.1186/1742-4690-5-100.PubMed CentralPubMedGoogle Scholar
  176. Yeung ML, Yasunaga J, Bennasser Y, Dusetti N, Harris D, Ahmad N, Matsuoka M, Jeang KT: Roles for microRNAs, miR-93 and miR-130b, and tumor protein 53-induced nuclear protein 1 tumor suppressor in cell growth dysregulation by human T-cell lymphotrophic virus 1. Cancer Res. 2008, 68: 8976-8985. 10.1158/0008-5472.CAN-08-0769.PubMed CentralPubMedGoogle Scholar
  177. Bellon M, Lepelletier Y, Hermine O, Nicot C: Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia. Blood. 2009, 113: 4914-4917. 10.1182/blood-2008-11-189845.PubMed CentralPubMedGoogle Scholar
  178. Zhou B, Wang S, Mayr C, Bartel DP, Lodish HF: miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA. 2007, 104: 7080-7085. 10.1073/pnas.0702409104.PubMed CentralPubMedGoogle Scholar
  179. Liu M, Yang L, Zhang L, Liu B, Merling R, Xia Z, Giam CZ: HTLV-1 Infection Leads to Arrest in the G1 phase of the Cell Cycle. J Virol. 2008, 82 (17): 8442-55. 10.1128/JVI.00091-08.PubMed CentralPubMedGoogle Scholar
  180. Tripp A, Liu Y, Sieburg M, Montalbano J, Wrzesinski S, Feuer G: Human T-cell leukemia virus type 1 tax oncoprotein suppression of multilineage hematopoiesis of CD34+ cells in vitro. J Virol. 2003, 77: 12152-12164. 10.1128/JVI.77.22.12152-12164.2003.PubMed CentralPubMedGoogle Scholar
  181. Liu B, Liang MH, Kuo YL, Liao W, Boros I, Kleinberger T, Blancato J, Giam CZ: Human T-lymphotropic virus type 1 oncoprotein tax promotes unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1 and causes chromosomal instability. Mol Cell Biol. 2003, 23: 5269-5281. 10.1128/MCB.23.15.5269-5281.2003.PubMed CentralPubMedGoogle Scholar
  182. Liu B, Hong S, Tang Z, Yu H, Giam CZ: HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule. Proc Natl Acad Sci USA. 2005, 102: 63-68. 10.1073/pnas.0406424101.PubMed CentralPubMedGoogle Scholar
  183. Kuo YL, Giam CZ: Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence. Embo J. 2006, 25: 1741-1752. 10.1038/sj.emboj.7601054.PubMed CentralPubMedGoogle Scholar
  184. Zhang L, Zhi H, Liu M, Kuo YL, Giam CZ: Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization. Retrovirology. 2009, 6: 35-10.1186/1742-4690-6-35.PubMed CentralPubMedGoogle Scholar
  185. Macleod KF, Sherry N, Hannon G, Beach D, Tokino T, Kinzler K, Vogelstein B, Jacks T: p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 1995, 9: 935-944. 10.1101/gad.9.8.935.PubMedGoogle Scholar
  186. Furukawa Y: Cell cycle control genes and hematopoietic cell differentiation. Leuk Lymphoma. 2002, 43: 225-231. 10.1080/10428190290005973.PubMedGoogle Scholar
  187. Cheng T, Rodrigues N, Dombkowski D, Stier S, Scadden DT: Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Nat Med. 2000, 6: 1235-1240. 10.1038/81335.PubMedGoogle Scholar
  188. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT: Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000, 287: 1804-1808. 10.1126/science.287.5459.1804.PubMedGoogle Scholar
  189. Jin DY, Spencer F, Jeang KT: Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell. 1998, 93: 81-91. 10.1016/S0092-8674(00)81148-4.PubMedGoogle Scholar
  190. Peloponese JM, Kinjo T, Jeang KT: Human T-cell leukemia virus type 1 tax and cellular transformation. Int J Hematol. 2007, 86: 101-106. 10.1532/IJH97.07087.PubMedGoogle Scholar
  191. Merling R, Chen C, Hong S, Zhang L, Liu M, Kuo YL, Giam CZ: HTLV-1 Tax mutants that do not induce G1 arrest are disabled in activating the anaphase promoting complex. Retrovirology. 2007, 4: 35-10.1186/1742-4690-4-35.PubMed CentralPubMedGoogle Scholar
  192. Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Jordan CT: Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001, 98: 2301-2307. 10.1182/blood.V98.8.2301.PubMedGoogle Scholar
  193. Ambrosini G, Adida C, Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997, 3: 917-921. 10.1038/nm0897-917.PubMedGoogle Scholar
  194. Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC, Altieri DC: Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol. 1999, 1: 461-466. 10.1038/70242.PubMedGoogle Scholar
  195. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998, 396: 580-584. 10.1038/25141.PubMedGoogle Scholar
  196. Fukuda S, Pelus LM: Elevation of Survivin levels by hematopoietic growth factors occurs in quiescent CD34+ hematopoietic stem and progenitor cells before cell cycle entry. Cell Cycle. 2002, 1: 322-326. 10.4161/cc.1.5.149.PubMedGoogle Scholar
  197. Fukuda S, Foster RG, Porter SB, Pelus LM: The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34(+) cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells. Blood. 2002, 100: 2463-2471. 10.1182/blood.V100.7.2463.PubMedGoogle Scholar
  198. Fukuda S, Mantel CR, Pelus LM: Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways. Blood. 2004, 103: 120-127. 10.1182/blood-2003-05-1756.PubMedGoogle Scholar
  199. Leung CG, Xu Y, Mularski B, Liu H, Gurbuxani S, Crispino JD: Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J Exp Med. 2007, 204: 1603-1611.PubMed CentralPubMedGoogle Scholar
  200. Kikuchi H, Ohtsuka E, Ono K, Nakayama T, Saburi Y, Tezono K, Ogata M, Iwahashi M, Nasu M: Allogeneic bone marrow transplantation-related transmission of human T lymphotropic virus type I (HTLV-I). Bone Marrow Transplant. 2000, 26: 1235-1237. 10.1038/sj.bmt.1702698.PubMedGoogle Scholar
  201. Matsuoka M, Green PL: The HBZ gene, a key player in HTLV-1 pathogenesis. Retrovirology. 2009, 6: 71-10.1186/1742-4690-6-71.PubMed CentralPubMedGoogle Scholar
  202. Usui T, Yanagihara K, Tsukasaki K, Murata K, Hasegawa H, Yamada Y, Kamihira S: Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells. Retrovirology. 2008, 5: 34-10.1186/1742-4690-5-34.PubMed CentralPubMedGoogle Scholar
  203. Tamiya S, Matsuoka M, Etoh K, Watanabe T, Kamihira S, Yamaguchi K, Takatsuki K: Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia. Blood. 1996, 88: 3065-3073.PubMedGoogle Scholar

Copyright

© Banerjee et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement