Genetic pathway in molecular pathogenesis of myelodysplastic syndrome (MDS) with AML1 point mutations

AML1点突变骨髓增生异常综合征（MDS）分子发病机制的遗传通路

• 批准号: 18591063
• 负责人: HARADA Yuka
• 金额: $ 2.57万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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-18591063/
• 关键词: Myelodysplastic syndrome; AML1; RUNX1; Hematopoietic stem cells; Partner gene mutations; Evil; MLL; Therapy related leukemia; Translocation; AML1; Evi1; エトポシド

AML1 mutations that have been reported to be frequent in myelodysplastic syndrome (MDS), especially in the therapy-related MDS and AML, are suspected to play a pivotal role for developing MDS/AML. We tried to analyze that radiation or anti-cancer drugs might induce the AML1 mutants in the hematopoietic stem cells. VP16-treated hematopoietic stem cells showed many gene rearrangements in their AML1 and MLL genes after 3 hours recovery, whereas non-VP16-treated cells also showed many of rearrangement bands after 2 weeks culture. These rearrangement bands were not detected in CEBPA gene, suggesting the sensitivity of gene rearrangements to VP16 are various among genes.Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We suspected that AML1-mutated hematopoietic stem cells might have genetic instability and might easily get partner gene mutations. We performed mouse bone marrow transplantation using bone marrow cells transduced with AML1 mutants. Most mice developed MDS/AML-like symptoms within several months after the transplant. The expression patterns of some genes have been changed by immigration of retrovirus vectors harboring AML1-mutations, and Evil seemed to collaborate with AML1 mutants to develop MDS/AML. We also tried to transduce AML1 mutation into human hematopoietic stem cells, and found their morphological changes and abnormal proliferation. Now we are inducing both AML1 mutant and partner gene mutant into human hematopoietic stem cells. Using this approach, we are able to clarify the molecular pathogenesis of MDS.

AML 1基因突变在骨髓增生异常综合征（MDS），尤其是治疗相关的MDS和AML中较为常见，被怀疑在MDS/AML的发生发展中起着关键作用。我们试图分析放射线或抗癌药物可能诱导造血干细胞发生AML 1突变。经VP 16处理的造血干细胞在培养3小时后，其AML 1和MLL基因出现了许多基因重排，而未经VP 16处理的造血干细胞在培养2周后也出现了许多重排条带。在CEBPA基因中未检测到这些重排条带，提示基因重排对VP 16的敏感性在不同基因间存在差异。虽然AML 1突变被认为在MDS/AML的发生中起关键作用，但获得额外的遗传改变也是必要的。我们怀疑AML 1突变的造血干细胞可能具有遗传不稳定性，容易发生伴侣基因突变。我们使用AML 1突变体转导的骨髓细胞进行小鼠骨髓移植。大多数小鼠在移植后几个月内出现MDS/AML样症状。携带AML 1突变的逆转录病毒载体的迁移改变了某些基因的表达模式，Evil似乎与AML 1突变体合作发展MDS/AML。我们还尝试将AML 1突变体导入人造血干细胞，发现其形态学改变和异常增殖。目前，我们正在将AML 1突变体和伴侣基因突变体同时导入人造血干细胞。使用这种方法，我们能够阐明MDS的分子发病机制。

项目成果

Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1-and p53-mediated transcription

• DOI: 10.1038/sj.onc.1210523
• 发表时间: 2007-11-08
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Li, X-L;Arai, Y.;Kitabayashi, I.
• 通讯作者: Kitabayashi, I.

AML1 mutations induced MDS and MDS/AML in a mouse BMT model

• DOI: 10.1182/blood-2007-01-068346
• 发表时间: 2008-04-15
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Watanabe-Okochi, Naoko;Kitaura, Jiro;Kitamura, Toshio
• 通讯作者: Kitamura, Toshio

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

セミパラチンスク核実験場近郊住民における骨髄異形成症候群(MDS)の遺伝子学的検討

塞米巴拉金斯克核试验场附近居民骨髓增生异常综合征（MDS）的遗传学研究

• 发表时间: 2008
• 期刊: 広島医学 61(4)
• 作者: Zharlyganova D;原田結花;原田浩徳;haizhunussova N;Apsalikov K;Zhunusova A;川野徳幸;星正治;木村昭郎
• 通讯作者: 木村昭郎

C/EBPα変異パターンによるAMLおよびMDS病型の解析

基于 C/EBPα 突变模式的 AML 和 MDS 疾病类型分析

• 发表时间: 2007
• 作者: 原田浩徳;原田結花;丁曄;許泰一;木村昭郎
• 通讯作者: 木村昭郎