Genetic pathway in molecular pathogenesis of myelodysplastic syndrome

骨髓增生异常综合征分子发病机制的遗传通路

• 批准号: 17590998
• 负责人: HARADA Hironori
• 金额: $ 2.3万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590998/
• 关键词: AML1; RUNX1; myelodysplastic syndrome (MDS); point mutation; RTK-RAS; second hit

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients. 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 analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with-7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of-5/5q-and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wildtype MDS/AML patients (38% versus 6.3%, P<.0001). Conversely, p.53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced ERK activation following SCF stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with-7/7q-alteration, and frequently involves RTK-RAS signaling pathway activation.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 these genes 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 continue this project. Furthermore, we found that CEBPA gene mutation is one of the master events to develop MDS/AML without AML1 mutation.

AML 1/RUNX 1突变在骨髓增生异常综合征（MDS）患者中经常报告。虽然AML 1突变被怀疑在MDS/AML的发展中起关键作用，但获得额外的遗传改变也是必要的。我们分析了AML 1突变的MDS/AML患者的基因改变，并将其与没有AML 1突变的患者的基因改变进行比较。AML 1突变与-7/7q-显著相关，而无AML 1突变的MDS/AML患者显示高频率的-5/5q-和复杂的核型。AML 1突变患者的FLT 3、N-RAS、PTPN 11和NF 1基因突变更多，导致AML 1突变MDS/AML患者的受体酪氨酸激酶（RTK）-RAS信号通路突变频率显著高于AML 1野生型MDS/AML患者（38% vs 6.3%，P<0.0001）。相反，p.53突变仅在无AML 1突变的患者中检测到。此外，表达表面c-KIT和SHP-2突变体的AML 1突变患者的母细胞有助于SCF刺激后ERK激活的延长和增强。我们的研究结果表明，AML 1/RUNX 1突变引起的MDS/AML与-7/7q-改变显著相关，并且经常涉及RTK-RAS信号通路的激活。大多数小鼠在移植后几个月内出现MDS/AML样症状。携带AML 1突变基因的逆转录病毒载体的移入改变了某些基因的表达模式，这些基因可能与AML 1突变体协同作用而发生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。现在我们继续这个项目。此外，我们发现CEBPA基因突变是发生无AML 1突变的MDS/AML的主要事件之一。

项目成果

Point mutations in the AML1/RUNXI gene associated with myelodysplastic syndrome.

与骨髓增生异常综合征相关的 AML1/RUNXI 基因点突变。

• 发表时间: 2005
• 期刊: Critical Reviews^<TM> in Eukaryotic Gene Expression 15(3)
• 作者: Harada H;et al.
• 通讯作者: et al.

Implications of somatic mutations in the AMLI/RUNXI gene in myelodysplastic syndrome (MDS) : Future molecular therapeutic directions for MDS.

AMLI/RUNXI 基因体细胞突变对骨髓增生异常综合征 (MDS) 的影响：MDS 的未来分子治疗方向。

• 发表时间: 2006
• 期刊: Current Cancer Drug Targets 6
• 作者: Harada H;et al.
• 通讯作者: et al.

AML1点異変を有する骨髄異形成症候群(MDS)の多段階発症メカニズムの解明

阐明具有 AML1 点突变的骨髓增生异常综合征 (MDS) 的多步发病机制

• 发表时间: 2006
• 期刊: 長崎医会誌 81・supp1
• 作者: Yano;H.;Komatsu H.;et al.;Kohara J.;Li Fu-Jun;原田浩徳 他
• 通讯作者: 原田浩徳 他

Point mutations in the AML1/RUNX1 gene associated with myelodysplastic syndrome (MDS).

与骨髓增生异常综合征 (MDS) 相关的 AML1/RUNX1 基因点突变。

• 发表时间: 2005
• 期刊: Acta Medica Nagasakiensia 50(suppl. 1)
• 作者: Harada H;et al.
• 通讯作者: et al.

別冊・医学のあゆみ血液疾患Ver.3-State of arts

单册：医学血液病史Ver.3-艺术现状

• 发表时间: 2005
• 作者: Takei;Y.;Mizukami;H.;Saga;Y.;Yoshimura;I.;Hasumi;Y.;Takayama;T.;Kohno;T.;Matsushita;T.;Okada;T.;Kume;A.;Suzuki;M.;Ozawa;K.;Kimura R;Kirito K et al.;原田浩徳(分担執筆)
• 通讯作者: 原田浩徳(分担執筆)