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  • Open Access

NDRG2 plays a pivotal role in ATLL leukaemogenesis by regulating the PTEN-mediated PI3K/AKT signalling pathway

  • 1,
  • 1,
  • 1,
  • 2,
  • 3,
  • 4 and
  • 1Email author
Retrovirology201411 (Suppl 1) :P87

https://doi.org/10.1186/1742-4690-11-S1-P87

  • Published:

Keywords

  • Promoter Methylation
  • Genetic Alteration
  • PTEN Expression
  • Candidate Tumour Suppressor
  • Candidate Tumour Suppressor Gene

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive T-cell leukemia/lymphoma that is etiologically linked to infection by human T-cell lymphotropic virus type 1 (HTLV-1). To find candidate causative genes for ATLL development, we used an integrative genomic analysis of ATLL and identified N-myc downstream-regulated gene 2 (NDRG2) as a candidate tumour suppressor gene on chromosome 14q11. Here we demonstrate that NDRG2 is a novel PTEN-interacting protein and recruits protein phosphatase 2A to facilitate the dephosphorylation of PTEN at the Ser380, Thr382, and Thr383 (STT) cluster within the C terminus. Although the PI3K/AKT signalling pathway is frequently activated in ATLL cells, neither the genetic alterations of the PTEN and PIK3CA genes nor the transcriptional down-regulation of PTEN expression were detected in ATLL. We found that activation of the PI3K/AKT signalling pathway in ATLL is mediated through hyperphosphorylation of PTEN-STT, a well-known mechanism of PTEN inactivation, by down-regulation of NDRG2 expression. Moreover, we found that NDRG2 deficiency in mice results in constitutive PI3K/AKT activation in various organs and high incidence of T-cell lymphoma and other types of cancer. Since down-regulation of NDRG2 expression via promoter methylation has been reported in various types of cancer, activation of the PI3K/AKT pathway by the enhanced PTEN-STT phosphorylation through the inactivation of NDRG2 is crucial for the development of a wide range of cancer cells including ATLL, which harbor no activating genetic alterations in the PI3K/AKT pathway.

Authors’ Affiliations

(1)
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Kiyotake, Miyazaki, Japan
(2)
Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
(3)
Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
(4)
Department of Molecular Hematology and Oncology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan

Copyright

© Nakahata et al; licensee BioMed Central Ltd. 2014

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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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