Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.
Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.
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DOI：
10.1016/j.stem.2015.09.017
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发表时间：
2015-12-03
期刊：
影响因子：
23.9
通讯作者：
Majeti R
中科院分区：
文献类型：
--
作者：
Mazumdar C;Shen Y;Xavy S;Zhao F;Reinisch A;Li R;Corces MR;Flynn RA;Buenrostro JD;Chan SM;Thomas D;Koenig JL;Hong WJ;Chang HY;Majeti R
在白血病前造血干细胞和急性髓性白血病及其他髓系恶性肿瘤的早期发展过程中，已经鉴定出粘附素复合物蛋白的复发性突变。虽然cohesins参与染色体分离和DNA损伤修复，但cohesin复合物在造血和白血病发展过程中的功能尚不清楚。在这里，我们表明，突变的粘附蛋白阻断分化的人造血干细胞和祖细胞（HSPC）在体外和体内，并执行干细胞程序。这些效应仅限于未成熟的HSPC群体，其中粘附素突变体显示染色质可及性增加，以及HSPC调节因子（包括ERG、GATA 2和RUNX 1）占用转录因子结合位点的可能性增加，如通过ATAC-seq和ChIP-seq测量的。上位性实验表明，沉默这些转录因子拯救了由粘着蛋白突变体引起的分化阻滞。总之，这些结果表明，突变的粘附蛋白通过控制染色质可及性和转录因子活性损害HSPC分化，可能有助于白血病疾病。
Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex function during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPC) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.