Genetic loss of SH2B3 in acute lymphoblastic leukemia
Genetic loss of SH2B3 in acute lymphoblastic leukemia
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DOI：
10.1182/blood-2013-05-500850
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发表时间：
2013-10-03
期刊：
影响因子：
20.3
通讯作者：
Ferrando, Adolfo A.
中科院分区：
文献类型：
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作者：
Perez-Garcia, Arianne;Ambesi-Impiombato, Alberto;Ferrando, Adolfo A.
SH 2B衔接蛋白3（SH 2B 3）基因编码细胞因子信号传导的负调节因子，在造血干细胞和淋巴祖细胞的稳态中具有关键作用。在这里，我们报告的生殖系纯合子SH 2B 3突变的鉴定与发育迟缓和自身免疫，其中一个兄弟姐妹B-前体急性淋巴细胞白血病（ALL）的发展。在NOTCH 1诱导的ALL小鼠模型中，SH 2B 3的缺失增加Janus激酶信号转导子和转录信号激活子，促进淋巴细胞增殖，并加速白血病的发展。此外，扩展突变分析显示，在分析的167例ALL中，有2例SH 2B 3纯合子体细胞突变。总体而言，这些结果表明，在ALL的发病机制中，SH 2B 3具有Knudson肿瘤抑制作用，并强调了自身免疫和白血病发生的发病机制中遗传易感因素之间的可能联系。
The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.