- Open Access
Elevated expression of CD30 in adult T-cell leukemia cell lines: possible role in constitutive NF-κB activation
© Higuchi et al; licensee BioMed Central Ltd. 2005
- Received: 07 February 2005
- Accepted: 06 May 2005
- Published: 06 May 2005
Human T-cell leukemia virus type 1 (HTLV-1) is associated with the development of adult T-cell leukemia (ATL). HTLV-1 encoded Tax1 oncoprotein activates the transcription of genes involved in cell growth and anti-apoptosis through the NF-κB pathway, and is thought to play a critical role in the pathogenesis of ATL. While Tax1 expression is usually lost or minimal in ATL cells, these cells still show high constitutive NF-κB activity, indicating that genetic or epigenetic changes in ATL cells induce activation independent of Tax1. The aim of this study was to identify the molecules responsible for the constitutive activation of NF-κB in ATL cells using a retroviral functional cloning strategy.
Using enhanced green fluorescent protein (EGFP) expression and blasticidin-resistance as selection markers, several retroviral cDNA clones exhibiting constitutive NF-κB activity in Rat-1 cells, including full-length CD30, were obtained from an ATL cell line. Exogenous stable expression of CD30 in Rat-1 cells constitutively activated NF-κB. Elevated expression of CD30 was identified in all ATL lines examined, and primary ATL cells from a small number of patients (8 out of 66 cases).
Elevated CD30 expression is considered one of the causes of constitutive NF-κB activation in ATL cells, and may be involved in ATL development.
- Enhance Green Fluorescent Protein
- Fluorescence Activate Cell Sorter Analysis
- Reporter Cell Line
- CD30 mRNA Expression
- Noncanonical Pathway
Adult T-cell leukemia (ATL) is an extremely aggressive human CD4+ T-cell leukemia (reviewed in ). ATL is resistant to chemotherapy and most patients die within one year of diagnosis. Human T-cell leukemia virus type 1 (HTLV-1) infection of CD4+ T-cells is the first step in ATL development. However, this alone is not sufficient for the development of leukemia because a minority of HTLV-1 infected subjects (approximately 5%) develop ATL on average 60–70 years after the infection (reviewed in [2, 3]). In vitro, HTLV-1 transforms primary human CD4+ T-cells in an interleukin (IL)-2-dependent or an IL-2-independent manner. HTLV-1 encoded Tax1 protein is thought to play a critical role in T-cell transformation and leukemogenesis, as Tax1 itself immortalizes primary human CD4+ T-cells in vitro [4, 5] and inhibits apoptosis induced by various stimuli in T-cell lines [6–9].
Tax1 is a multifunctional protein (reviewed in [2, 3]). It activates the transcription of many cellular genes associated with cell growth, such as genes encoding cytokines [10–13], cytokine receptors [14–17], anti-apoptotic protein [8, 18], cell cycle regulators [19–22], and proto-oncogenes . Those proteins are thought to contribute to the deregulated proliferation of HTLV-1-infected cells. Accumulating evidence suggests that activation of cellular genes by Tax1, particularly through the nuclear factor-kappaB (NF-κB) pathway, is a critical process in transformation as well as the inhibition of apoptosis. For example, the transforming activity of Tax1 is abrogated by mutations that impair the ability of Tax1 to activate NF-κB [24–26]. Tax1 inhibits apoptosis of mouse T-cell lines by induction of the anti-apoptotic gene Bcl-xL through NF-κB activation [8, 18].
In resting T-cells, NF-κB factors are sequestered in the cytoplasm, tightly associated with inhibitory proteins IκBs. Activation of NF-κB generally involves phosphorylation and degradation of IκBs, followed by nuclear translocation of NF-κB dimers and subsequent activation of the genes containing NF-κB binding sites (reviewed in ). Alternatively, NF-κB activation occurs by inducible processing of NFKB2/p100 with IκB-like inhibitory activity, into p52 with DNA binding activity, followed by nuclear translocation of p52 containing NF-κB dimers (reviewed in ). These two processes are largely dependent on an IκB kinase (IKK) complex comprised of two catalytic subunits, IKKα and IKKβ and a regulatory subunit IKKγ/NEMO. Tax1 interacts with the IKK complex through these three subunits and stimulates the catalytic activity [29–32].
In primary ATL cells as well as cell lines established from ATL patients, NF-κB is constitutively active as seen in HTLV-1 transformed cells . It appears that this constitutive NF-κB activation contributes to the survival and chemotherapy resistance of ATL cells, since treatment of ATL cells with a NF-κB inhibitor, Bay 11-7082, induces apoptosis of these cells . However, how NF-κB is constitutively activated in ATL cells is still largely unknown since the tax gene is mutated in some ATL cases [35, 36] or the level of expression of Tax1 in these cells is extremely low, thereby being clearly insufficient to activate NF-κB [37, 38]. There may be genetic or epigenetic changes that lead to tax-independent NF-κB activation, such as a gain of function of the NF-κB activating molecule(s) or a loss of function of the NF-κB regulator(s). The elucidation of the molecular mechanism of NF-κB activation in ATL cells is quite important in the light of prevention, diagnosis and treatment of ATL.
In order to identify the molecule(s) responsible for the constitutive NF-κB activation in ATL, we took a functional screening approach using a retroviral cDNA library from an ATL cell line and a reporter cell line that is easily distinguishable as a positive clone once NF-κB is activated. We obtained several cDNA clones that constitutively activate NF-κB. One of these, the full-length CD30, is a member of the TNF receptor superfamily and a marker of malignant Hodgkin and Reed-Sternberg (H-RS) cells in Hodgkin's lymphoma (HL) (reviewed in [39, 40]). It is suggested that overexpression of CD30 in H-RS cells and HL cell lines contributes to CD30 ligand-independent constitutive NF-κB activation in these cells . The results showed that CD30 is strongly expressed in all ATL cell lines examined, and that CD30 is expressed in primary ATL cells in a small number of ATL patients.
Screening of NF-κB activating molecules
NF-κB activators isolated from the TL-OmI cDNA library.
No. of isolates
N terminal deletion
NF-κB inducing kinase (NIK) is a mitogen-activated protein kinase kinase kinase (MAP3K), which is involved in NFKB2/p100 processing and nuclear translocation of p52/RelB dimers, the so-called noncanonical pathway . This pathway is activated by lymphotoxin-β (LT-β), CD40 ligand, and B cell activating factor (BAFF) and depends on IKKβ (reviewed in ). All the NIK clones we obtained possessed the intact kinase domain and the N-terminal amino acid deletion, starting at codon 417. It has been reported that the N-terminus of NIK contains a negative-regulatory domain and an N-terminal truncation mutant has higher NF-κB inducing activity than the wild type . It is likely that this deletion was introduced by incomplete reverse transcription with oligo dT primer during the cDNA library construction process. It is interesting to note that none of the other MAP3Ks that can activate NF-κB, such as MEKK1 , were cloned. This selective isolation of NIK as well as its high frequency among the NF-κB-inducing clones indicates that NIK and/or the noncanonical pathway may play a central role in the constitutive NF-κB activation seen in various tumors.
The sequences of the two LT-β receptor (LT-βR) clones were identical and encoded a part of the cytoplasmic domain of the receptor (from codon 268 to 395). The retrovirus vector used in our experiments transcribes two mRNAs, one spliced and one unspliced. The unspliced mRNA may translate fusion genes of gag with inserted cDNA when they are in frame. The isolated LT-βR clone is in frame with gag and could be expressed as a fusion protein, which might induce constitutive NF-κB activation. This cloned LT-βR mutant is likely to be an artificial one generated during the library construction process as discussed above.
The receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that contains a caspase-recruitment domain (CARD) at its carboxyl terminus and has been shown to induce NF-κB activation in an over-expression system . Rip2 has been implicated in regulating both the innate and adaptive immune responses [47, 48]. Recently, it has been reported that Rip2 participates in Bcl10-mediated NF-κB activation . The Rip2 clone isolated in our study is full length and not in frame with gag. It is possible that Rip2 is over-expressed in ATL cells and this contributes to constitutive NF-κB activation. This hypothesis is currently under investigation.
Exogenous stable expression of CD30 induces constitutive NF-κB activation
Overexpression of CD30 in ATL cell lines
Expression of CD30 in primary ATL cells
Cell surface markers in CD30-positive ATL cases
% of Positive Cells
The reason for the discrepancy between ATL cell lines and primary ATL cells in terms of CD30 expression is unknown at present. One possibility is that only CD30-positive primary ATL cells could be established as a cell line in vitro because of their stronger NF-κB activity or activation of other signaling pathways originating from CD30. In fact, CD30 activates not only NF-κB but also the mitogen activated protein kinase (MAPK) pathways, such as extracellular regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 MAPK pathways [53, 54].
Recently, it has been reported that the noncanonical pathway is involved in constitutive NF-κB activation in ATL cells . Although activation of the noncanonical pathway by CD30 has not yet been reported, it is likely that CD30 activates this pathway through association with TNF receptor associated factors (TRAFs) like LT-βR and CD40. In H-RS cells, which strongly express CD30, TRAF2 and TRAF5 make aggregates in the cytoplasm and co-localize with downstream signaling molecules, such as IKKα and IKKβ . It would be interesting to see whether TRAF2 and TRAF5 also form aggregates in ATL cell lines and primary ATL cells expressing CD30.
In order to confirm that CD30 is involved in constitutive NF-κB activation and cell survival in ATL cell lines, we tried to knockdown CD30 expression in these cells by using short-hairpin RNAs. We generated 11 different short-hairpin RNAs for CD30 in total, but none of them showed any RNA interference effect. We also tried to introduce a decoy CD30 that lacks most of the cytoplasmic region and has been shown to induce apoptosis in H-RS cells , by using an adenovirus vector. However we were unable to obtain a sufficiently high titer adenovirus as a decoy CD30 mutant to carry out the experiment. Thus, whether elevated expression of CD30 actually contributes to constitutive NF-κB activation in ATL cell lines still remains unknown.
In this regard, the mechanism by which NF-κB is constitutively activated in ATL cells still remains a mystery. However, our data suggest that the elevated expression of CD30 plays a critical role in NF-κB activation in ATL cell lines and a small number of primary ATL cells. Other molecules belonging to the TNF receptor family, such as LT-βR, OX40, or downstream signaling molecules, could be involved in constitutive NF-κB activation in CD30-negative ATL cells, and the identification of such molecules would contribute to the prevention, diagnosis and treatment of ATL.
ATL cells have constitutive NF-κB activity which is important for the cells' survival. This NF-κB activation is independent of Tax protein expression. By screening a retroviral cDNA library from an ATL cell line to identify NF-κB activating molecules, we obtained several cDNA clones including full-length CD30. CD30 is strongly expressed in ATL cell lines and primary ATL cells from a small number of patients. Our results suggest that elevated expression of CD30 is one of the factors responsible for constitutive NF-κB activation in ATL cells.
Rat-1, a rat fibroblast cell line, was cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). Human T-cell lines used in the present experiments have been characterized previously [33, 57]. Jurkat and MOLT-4 are HTLV-1 negative human T-cell lines. HUT-102, C5/MJ, MT-4 and SLB-1 are HTLV-1-positive human T-cell lines. TL-OmI, KK1 , KOB , and ST1  are HTLV-1-positive, ATL-derived cell lines. These cells were cultured in RPMI 10% FBS. Recombinant human IL-2 (Takeda Chemical Industries, Osaka, Japan) was added at 0.5 nM to the culture of KK1, KOB and ST1. A retrovirus packaging cell line Plat-E  was cultured in DMEM 10% FBS containing 1 μg/ml puromycin (Calbiochem, La Jolla, CA) and 10 μg/ml blasticidin (Invitrogen, San Diego, CA).
cDNA library construction
Poly (A)+ RNA was purified from TL-OmI using FastTrack 2.0 (Invitrogen). cDNA was synthesized by oligo(dT) primers using SuperScript Choice System (Invitrogen) according to the instructions provided by the manufacturer. The resulting cDNAs were size-fractionated through agarose gel electrophoresis, and cDNA fragments longer than 2.5 kb were extracted from the gel by using Qiaex II (Qiagen, Hilden, Germany). The cDNA fragments were then inserted into BstXI sites of the retroviral vector pMX  using BstXI adapters (Invitrogen). The ligated DNA was ethanol-precipitated and then electroporated into DH10B competent cells (Electromax DH10B; Invitrogen). About 1 × 106 independent clones were amplified on 150 mm LB/amp plates and plasmid DNA was purified by using Qiagen Plasmid Giga kit (Qiagen).
Generation of a reporter cell line
The NF-κB reporter plasmid κB-EGFP was constructed by replacing the luciferase gene (a BglII – BamHI fragment) of the κB-Luc plasmid  with EGFP (a HindIII – AflII fragment) from pEGFP-N3 (Clontech Laboratories, Palo Alto, CA) by blunt-end ligation. To construct the plasmid κB-bsrEGFP, which expresses bsrEGFP fusion protein, a PCR amplified bsr gene fragment was inserted in the ApaI and BamHI sites upstream of EGFP of the κB-EGFP plasmid. To prepare a NF-κB reporter cell line, Rat-1 cells (5 × 106) were transfected with 20 μg of κB-bsrEGFP and 1 μg of pcDNA3 (Invitrogen) by electroporation at 250 V and 975 μF. The transfected cells were cultured in 500 μg/ml G418 (Invitrogen), and resistant clones were screened for EGFP signals after being infected with retroviruses that express Epstein-Barr virus transforming protein LMP1. The selected cell clone (Rat-1 κB-bsrEGFP) was further transfected with κB-EGFP and pMik-HygB and cultured in 250 μg/ml hygromycin B (Wako Pure Chemical Industries, Osaka, Japan). Resistant clones were screened for EGFP signals after stimulation with 20 ng/ml TNF-α (Peprotech, London, UK).
Preparation of retroviruses and infection of reporter cells
Plat-E cells (2 × 106 cells) were seeded onto 60 mm dishes one day before transfection. The cDNA library (3 μg) was transfected using Fugene 6 (Roche Molecular Systems, Inc., NJ) according to the protocol provided by the manufacturer. Cells were cultured for 48 hours and the retroviral supernatant was harvested. For infection of reporter cells, 2.5 × 105 cells were seeded onto 100 mm dishes one day before infection and incubated with 10 ml DMEM 10% FBS containing 0.6 ml of the virus stock for 24 hours in the presence of polybrene (20 μg/ml). The medium was changed to fresh DMEM 10% FBS after 24 hours. After another 24 hours, the cells were incubated with medium containing 50 μg/ml blasticidin (Invitrogen).
Isolation of cDNA fragments from blasticidin-resistant clones
Genomic DNA was extracted from the blasticidin-resistant clones by DNeasy kit (Qiagen) and subjected to PCR to recover integrated cDNAs using pMX vector primers (5'-GGTGGACCATCCTCTAGACT-3' and 5'-CCCCTTTTTCTGGAGACTAAAT-3'). The PCR products were cloned into pGEM-T Easy vector (Promega, Madison, WI) and sequenced using BigDye Terminator v1.1 cycle sequencing kit (Applied Biosystems, Foster City, CA).
The retroviral vector pMX LMP1 was prepared by inserting an EcoRI – BamHI fragment of pSG5 F-LMP1  in the EcoRI site of pMX by blunt-end ligation. pMX CD30WT was generated by inserting a MluI – NotI fragment of pCD30WT  in the EcoRI and NotI sites of pMX by blunt-end ligation. pMX kBL1 was generated by inserting a BamHI – SfiI fragment of pGEMT kBL1 in the BamHI – NotI sites of pMX. The BglII site of pMX kBL1 was destroyed by cutting by BglII, filling in by T4 polymerase, and self-ligation to make pMX kBL1ΔBglII.
Flow cytometric analysis
Heparinized peripheral blood, a piece of a lymph node, or ascites (in case no. 8) was collected from patients with ATL after obtaining informed consent in accordance with the Helsinki Declaration. Mononuclear cells were separated by Lymphoprep™ density gradient centrifugation (Axis-Shield PoC AS, Oslo, Norway). Morphological and surface marker analyses indicated that ATL cells in these samples always accounted for more than 80% of the total cell population in most cases. The study protocol was approved by the Human Ethics Review Committee of Nagasaki University Graduate School of Biomedical Sciences.
Primary ATL cells or T-cell lines were incubated for 30 min at 4°C with each PE-labeled or FITC-labeled monoclonal antibody (mAb). Cells were also incubated with isotype matched control antibodies. The following antibodies were used: PE-labeled mouse anti-human CD4 and CD25, FITC-labeled anti CD3 and CD8 (BD Biosciences Pharmingen, San Diego, CA); and PE-labeled mouse anti-human CD30 (Dako Corporation, Carpinteria, CA or Immunotech, Marseille, France). After washing with PBS, the cells were analyzed on FACScan flow cytometer using Cellquest software (Becton Dickinson, San Jose, CA).
Reverse transcription-polymerase chain reaction
Total cellular RNA was extracted with Trizol (Invitrogen) according to the protocol provided by the manufacturer. First-strand cDNA was synthesized from 1 μg total cellular RNA in a 20-μl reaction volume using an RNA PCR kit (Takara Shuzo, Kyoto, Japan) with random primers. Thereafter, cDNA was amplified for 35 cycles for CD30 and 28 cycles for β-actin. The oligonucleotide primers used were as follows: for CD30, sense, 5'-CTGTGTCCCCTACCCAATCT-3' and antisense, 5'-CTTCTTTCCCTTCCTCTTCCA-3';  and for β-actin, sense, 5'-GTGGGGCGCCCCAGGCACCA-3' and antisense, 5'-CTCCTTAATGTCACGCACGATTTC-3'. Product sizes were 860-bp for CD30 and 548-bp for β-actin. Cycling conditions were as follows: denaturing at 94°C for 45 sec (for CD30) or for 30 sec (for β-actin), annealing at 62°C for 45 sec (for CD30) or 60°C for 30 sec (for β-actin) and extension at 72°C for 60 sec (for CD30) or for 90 sec (for β-actin). The PCR products were fractionated on 2% agarose gels and visualized by ethidium bromide staining.
We are deeply indebted to the many patients with ATL and the control subjects who donated blood for these studies. We thank T. Kitamura for providing the retroviral vector pMX and the packaging cell line Plat-E. We also thank R. Fujita, S. Takizawa, and C. Yamamoto for the excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research of Japan, Grant for Promotion of Niigata University Research Projects, and Tsukada Grant for Niigata University Medical Research.
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