Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
J Exp Med. 2018 Jun 4;215(6):1729-1747. doi: 10.1084/jem.20171151. Epub 2018 Apr 11.
() is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.
（）在髓系恶性肿瘤和不确定潜能的克隆性造血（CHIP）中经常发生突变。尽管 ASXL1 的缺失会促进造血转化，但越来越多的证据表明突变可能会导致功能改变。在这项研究中，我们使用条件敲入（KI）在体内鉴定出一种 C 端截断的 Asxl1 突变体的生理表达导致髓系偏向、年龄相关的贫血、血小板增多和形态发育不良。虽然突变型 Asxl1 表达改变了造血干细胞（HSCs）的功能，但它在竞争性移植实验中维持了它们的存活，并通过共同发生突变或病毒插入诱变增加了白血病转化的易感性。KI 小鼠表现出 H3K4me3 和 H2AK119Ub 的大量减少，而 H3K27me3 没有明显减少，与 Asxl1 缺失的影响不同。染色质免疫沉淀结合下一代测序分析表明野生型和突变型 Asxl1 对 H3K4me3 有相反的影响。这些发现表明突变赋予 HSCs 改变的表观基因组，并增加白血病转化的易感性，为 CHIP 提供了一个新的模型。
