Analysis on the molecular mechanisms for the self renewal of the leukemic stem cells and for the leukemcgenesis

白血病干细胞自我更新及白血病发生的分子机制分析

• 批准号: 18390278
• 负责人: NOSAKA Tetsuya
• 金额: $ 11.25万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390278/
• 关键词: leukemic stem cell; 11q23 chromosomal translocation; MLL; infant leukemia; Ras; mouse bone marrow transplantation; retroviral vector; Hox; 白血病肝細胞; Raf; MAPK; STAT5

A variety of reciprocal 11q23 translocations generating fusions of MLL(Mixed Lineage Leukemia) with partner genes are frequently found in infant acute leukemia. However, little has been clarified regarding the pathway through which MLL fusion proteins lead to leukemia. We have recently reported the two-step leukemogenesis by MLL fusion proteins in mice models(Ono R, et. al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J. Clin. Invest 115, 919-929, 2005 ; selected as one of the highlight papers in the April 2005 issue of the Nature Reviews/Cancer). By comparing the effects of two kinds of FLT3 mutants, and constitutively active mutant molecules of Ras, Raf, and STATS, we first identified Ras/Raf/MAPK as synergistic collaborative pathway for MLL fusion proteins to induce acute leukemia. Furthermore, expression of Hoxa9, one of the upregulated molecules in MLL-related human leukemia, and Ras activation were found to recapitulate MLL-fusion-mediated acute leukemia in mice. Hoxa9 is considered to contribute to confer self-renewal activity on leukemic cells, and Ras activation is inferred to induce proliferation of the leukemic cells.Thus this study unveiled the molecular mechanism of MLL-fusion-mediated leukemogenesis, and may help develop the MLL-fusion-targeted therapy in future.

在婴儿急性白血病中经常发现多种11q23易位，导致MLL(混合血统白血病)与伴侣基因的融合。然而，关于MLL融合蛋白导致白血病的途径尚不清楚。我们最近报道了MLL融合蛋白在小鼠模型(OnoR，et.)中的两步致白血病作用。艾尔MLL融合蛋白的二聚化和Flt3的激活协同诱导多系白血病的发生。J·克莱恩。投资115,919-929,2005；被选为2005年4月刊《自然评论/癌症》的重点论文之一)。通过比较两种Flt3突变体以及Ras、Raf和STATS的结构活性突变分子的作用，我们首次确定Ras/Raf/MAPK是MLL融合蛋白诱导急性白血病的协同作用途径。此外，MLL相关的人类白血病中上调的分子之一Hoxa9的表达和RAS的激活被发现概括了MLL融合介导的小鼠急性白血病。Hoxa9被认为有助于赋予白血病细胞自我更新活性，RAS激活可能诱导白血病细胞的增殖，因此本研究揭示了MLL融合介导的白血病发生的分子机制，并可能有助于未来MLL融合靶向治疗的发展。

项目成果

Human parainfluenza virus type 2 V protein inhibits genome replication by binding to the L protein; a possible role in promoting viral fitness.

人副流感病毒2型V蛋白通过与L蛋白结合抑制基因组复制；

• 发表时间: 2008
• 期刊: Journal of Virology (印刷中)
• 作者: Nishio M;Ohtsuka J;Tsurudome M;Nosaka T;Kolakofsky D.
• 通讯作者: Kolakofsky D.

C/EBPα and C/EBPε induce monocytic differentiation of myelomonocytic cells with MLL chimeric fusion gene

C/EBPα和C/EBPε利用MLL嵌合融合基因诱导骨髓单核细胞的单核细胞分化

• 发表时间: 2006
• 作者: Matsushita H;Nakajima H;Nakamura Y;Tsukamoto H;Tanaka Y;Asai S;Nosaka T;Ando K;Miyachi H
• 通讯作者: Miyachi H

RasGRP4 と変異型AML1はマウスBMTモデルにおいて協調的に働き、T細胞性白血病を誘発する

RasGRP4 和突变 AML1 在小鼠 BMT 模型中协同诱导 T 细胞白血病

• 发表时间: 2007
• 作者: Asou;H.;Nagamachi;A.;Honda;H^<*1>.;Ozald;Y.;Matsui;H.;Aki;D.;Fujioka;K.;Inaba;T;松井 啓隆;麻生 博也;王 月;松井 啓隆;渡辺(大河内)直子
• 通讯作者: 渡辺(大河内)直子

Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD

• DOI: 10.1038/sj.leu.2404883
• 发表时间: 2007-11-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Lu, Y.;Kitaura, J.;Kitamura, T.
• 通讯作者: Kitamura, T.

Identification of leukemia-related gene alterations: Molecular pathogenesis of leukemia, myeloproliferative disorders(MPD), and myelodysplastic syndromes(MDS).

白血病相关基因改变的鉴定：白血病、骨髓增殖性疾病 (MPD) 和骨髓增生异常综合征 (MDS) 的分子发病机制。

• 发表时间: 2008
• 期刊: Blood Cells, Molecules and Diseases. (印刷中)
• 作者: Kitamura T;Oki T;Watanabe-Okochi N;Komeno Y;Kato N;Yuji K;Ono RNakajima H;Tojo A;Nosaka T;Kitaura J.
• 通讯作者: Kitaura J.