ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion.
ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion.
复制标题
ASXL2调节小鼠的造血，其缺乏促进髓样膨胀。
DOI：
10.3324/haematol.2018.189928
复制
发表时间：
2018-12
期刊：
影响因子：
10.1
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Madan V;Han L;Hattori N;Teoh WW;Mayakonda A;Sun QY;Ding LW;Nordin HBM;Lim SL;Shyamsunder P;Dakle P;Sundaresan J;Doan NB;Sanada M;Sato-Otsubo A;Meggendorfer M;Yang H;Said JW;Ogawa S;Haferlach T;Liang DC;Shih LY;Nakamaki T;Wang QT;Koeffler HP
在大约10%的急性髓性白血病（AML）中观察到染色体易位t(8;21)（q22;q22）导致致癌RUNX1-RUNX1T1 （AML1-ETO）融合的产生。为了确定与t（8;21）驱动白血病相关的体细胞突变，我们对一个亚洲队列在诊断和复发时进行了全基因组和靶向外显子组测序。我们发现在这种AML亚型中，ASXL2的截断性改变以及KIT、TET2、MGA、FLT3和DHX15的复发性突变的频率很高。为了深入研究ASXL2在正常造血中的作用，我们使用了ASXL2缺乏的小鼠模型。在移植模型中，ASXL2缺失导致以骨髓增生、脾肿大、髓外造血和重建能力差为特征的进行性造血缺陷。对幼龄和1岁以上asx12缺陷小鼠的平行分析显示，年龄依赖性扰动不仅影响髓系和红系分化，还影响淋巴样细胞的成熟。总的来说，这些发现确立了ASXL2在维持稳态造血中的关键作用，并提供了ASXL2缺失如何启动髓细胞扩张的见解。
Chromosomal translocation t(8;21)(q22;q22) which leads to the generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in approximately 10% of acute myelogenous leukemia (AML). To identify somatic mutations that co-operate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis, and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting, not only myeloid and erythroid differentiation, but also maturation of lymphoid cells. Overall, these findings establish a critical role for ASXL2 in maintaining steady state hematopoiesis, and provide insights into how its loss primes the expansion of myeloid cells.