Analysis of autoimmune mechanisms of myelodysplastic syndromes

骨髓增生异常综合征的自身免疫机制分析

• 批准号: 25670446
• 负责人: OGAWA Seishi
• 金额: $ 2.41万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2013
• 资助国家: 日本
• 起止时间: 2013-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-25670446/
• 关键词: 骨髄異形成症候群; 自己免疫; HLAテトラマー

It was well known that many patients with aplastic anemia (AA) develop clonal disorders including myelodysplastic syndromes (MDS). Although the underlying mechanism is poorly understood, some escape from cytotoxic T-cells involved in AA pathogenesis is implicated in the progression to MDS. In this study, through a comprehensive analysis of somatic mutations in AA, we identified frequent somatic mutations of a wide variety of genes in as many as 60% of patients with AA. Some mutations affected known mutational targets in MDS, such as DNMT3A, ASXL1, and BCOR. Our results may indicated that these mutational targets could represent common targets of CTLs in AA, which when mutated, involved not only in escaping from CTL but also in clonal selection in MDS. It should be warranted in future studies to test whether these mutational targets encode common epitopes that are recognized by CTLs in AA.

众所周知，许多再生障碍性贫血（AA）患者会出现包括骨髓增生异常综合征（MDS）在内的克隆性疾病。尽管潜在的机制尚不清楚，但参与AA发病机制的细胞毒性t细胞的一些逃逸与MDS的进展有关。在本研究中，通过对AA患者体细胞突变的综合分析，我们发现多达60%的AA患者存在多种基因的频繁体细胞突变。一些突变影响MDS中已知的突变靶点，如DNMT3A、ASXL1和BCOR。这些突变靶点可能代表了AA中CTL的共同靶点，当这些靶点发生突变时，不仅参与逃离CTL，还参与MDS的克隆选择。在未来的研究中，有必要测试这些突变靶点是否编码了AA中ctl识别的共同表位。

项目成果

Spectrum of genetic alterations in acquired aplasticanemia

获得性再生障碍性贫血的遗传改变谱

• 发表时间: 2013
• 作者: 吉里哲一;小川誠司 et al.
• 通讯作者: 小川誠司 et al.

Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.

• DOI: 10.1038/leu.2013.336
• 发表时间: 2014-02
• 期刊: Leukemia
• 影响因子: 11.4

Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders.

• DOI: 10.1084/jem.20131144
• 发表时间: 2013-11-18
• 期刊: The Journal of experimental medicine
• 作者: Muto T;Sashida G;Oshima M;Wendt GR;Mochizuki-Kashio M;Nagata Y;Sanada M;Miyagi S;Saraya A;Kamio A;Nagae G;Nakaseko C;Yokote K;Shimoda K;Koseki H;Suzuki Y;Sugano S;Aburatani H;Ogawa S;Iwama A
• 通讯作者: Iwama A

Somatic SETBP1 mutations in myeloid malignancies.

• DOI: 10.1038/ng.2696
• 发表时间: 2013-08
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Makishima, Hideki;Yoshida, Kenichi;Nhu Nguyen;Przychodzen, Bartlomiej;Sanada, Masashi;Okuno, Yusuke;Ng, Kwok Peng;Gudmundsson, Kristbjorn O.;Vishwakarma, Bandana A.;Jerez, Andres;Gomez-Segui, Ines;Takahashi, Mariko;Shiraishi, Yuichi;Nagata, Yasunobu;Guinta, Kathryn;Mori, Hiraku;Sekeres, Mikkael A.;Chiba, Kenichi;Tanaka, Hiroko;Muramatsu, Hideki;Sakaguchi, Hirotoshi;Paquette, Ronald L.;McDevitt, Michael A.;Kojima, Seiji;Saunthararajah, Yogen;Miyano, Satoru;Shih, Lee-Yung;Du, Yang;Ogawa, Seishi;Maciejewski, Jaroslaw P.
• 通讯作者: Maciejewski, Jaroslaw P.

Spectrum of genetic alterations in acquired aplastic anemia

获得性再生障碍性贫血的遗传改变谱

• 发表时间: 2013
• 作者: 吉里哲一;小川誠司 et al.,
• 通讯作者: 小川誠司 et al.,