| Project/Area Number |
21390098
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pathological medical chemistry
|
|---|
| Research Institution | University of Miyazaki |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TANIWAKI Masafumi 京都府立医科大学, 医学部, 教授 (80163640)
NAKAHATA Shingo 宮崎大学, 医学部, 助教 (80437938)
NISHIKATA Ichiro 宮崎大学, 医学部, 助教 (50253844)
中尾 和貴 独立行政法人理化学研究所, 動物資源開発室動物実験支援ユニット, ユニットリーダー (20217657)
山川 哲生 宮崎大学, 医学部, 助教 (60335825)
|
|---|
| Project Period (FY) |
2009 – 2011
|
| Project Status |
Completed (Fiscal Year 2011)
|
| Budget Amount *help |
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2011: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2009: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
|
|---|
| Keywords | TSLC1/CADM1/IgSF4 / TCF8(ZEB1) / NDRG2 / 成人T細胞白血病(ATL) / BCL11B / 癌 / 遺伝子 / ゲノム / 成人T細胞白血病 / TCF8/ZEB1 / TSLC1 / CADM1 / IgSF4 / TCF8 / ZEB1 |
|---|
| Research Abstract |
To elucidate the mechanism of multistep leukemogenesis of adult-T cell leukemia(ATL) after HTLV-1 infection, we performed an integrated genomic analysis of ATL using spectral karyotyping(SKY), high density SNP array, and DNA microarray. As a result, we identified three translocation breakpoint cluster regions(10p11, 14q11, and 14q32) and found TCF8(ZEB1) at chromosome 10p11, NDRG2 at 14q11, and BCL11B at 14q32 as candidate tumor suppressor genes. Using genome-wide gene expression profiles, we also identified TSLC1 as a novel cell surface marker for ATL. We demonstrated that downregulation of TCF8 with upregulation of Smad7 renders ATL cells resistance to TGFbeta and downregulation of NDRG2 is a major cause of constitutive PI3K/AKT activation, and that overexpression of TSLC1 is associated with organ infiltration of ATL cells. The majority of TCF8-deficient and TSLC1-transgenic mice developed T-lymphoma with multiple organ invasions and a wide variety of cancers including T-cell lymphoma were developed in NDRG2-deficient mice. Therefore, this study opens the way to resolve multistep leukemogenesis of ATL and may lead to the development of novel methods of molecular diagnosis and strategies of effective molecular-targeted therapies.
|
