Hematopoietic transformation in the absence of MLL1/KMT2A: distinctions in target gene reactivation.
Hematopoietic transformation in the absence of MLL1/KMT2A: distinctions in target gene reactivation.
复制标题
MLL1/KMT2A 缺失下的造血转化：靶基因重新激活的差异。
DOI：
10.1080/15384101.2019.1618642
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Ernst,Patricia
中科院分区：
文献类型：
--
作者：
Chen,Yufei;Ernst,Patricia
The deregulation of hematopoietic stem cell (HSC) transcriptional networks is a common theme in acute myelogenous leukemia (AML). Chromosomal translocations that alter theMixed Lineage Leukemia 1gene (MLL1, MLL, KMT2A) occur in infant, childhood and adult leukemia and at the same time, wild-type MLL1 is a critical regulator of HSC homeostasis. Typically, the endogenous, wild-type (WT) MLL1 and MLL fusion oncoproteins (MLL-FPs) remain both expressed in leukemia. WT and MLL-FPs activate overlapping sets of target genes, presenting a challenge for the selective therapeutic targeting of leukemic cells. We previously demonstrated that endogenous MLL1 is not required for the maintenance of MLL-FP-driven AML but is required for normal HSC homeostasis. Here we address the role of MLL-FPs in the initiation of leukemia in the absence of endogenous MLL1. We show that loss of endogenousMll1results in a rapid decrease in expression of shared HSC/leukemia target genes, yet MLL-AF9 restores the expression of most of these target genes in the absence of WT MLL1, with the critical exception ofMecom/Evi1. These observations underscore the sufficiency of MLL-fusion oncoproteins for initiating leukemia, but also illustrate that WT MLL1 target genes differ in their ability to be re-activated by MLL-FPs.
