Analysis of ATL leukemogenesis through breakage of defense mechanism of HTLV-1 infection

2015 Fiscal Year Final Research Report

• Project/Area Number: 25293081
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University of Miyazaki
• Principal Investigator: Kazuhiro Morishita 宮崎大学, 医学部, 教授 (80260321)
• Co-Investigator(Kenkyū-buntansha): TANIWAKI Masfumi 京都府立医科大学, 医学研究科, 教授 (80163640) ; NAKAHATA Shingo 宮崎大学, 医学部, 助教 (80437938) ; ICHIKAWA Tomonaga 宮崎大学, 医学部, 助教 (80586230) ; KANEDA Kazuko 宮崎大学, 医学部, 助教 (00533209) ; NISHIKATA Ichiro 宮崎大学, 医学部, 助教 (50253844)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: HTLV-1 / 成人T細胞白血病 / NDRG2 / PTEN

Outline of Final Research Achievements

Constitutive PI3K/AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that NDRG2 is a PTEN-binding protein that recruits protein phosphatase 2A (PP2A) to PTEN. The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in NDRG2-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.

Free Research Field

分子生物学。血液学