Author:
Shields Benjamin J.,Jackson Jacob T.,Metcalf Donald,Shi Wei,Huang Qiutong,Garnham Alexandra L.,Glaser Stefan P.,Beck Dominik,Pimanda John E.,Bogue Clifford W.,Smyth Gordon K.,Alexander Warren S.,McCormack Matthew P.
Abstract
Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16INK4a and p19ARF, which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.
Funder
Program grant
Project grants
Independent Research Institutes Infrastructure Support (IRIIS) Scheme
Australian Government's National Health and Medical Research Council
Cancer Council of Victoria
Leukemia Foundation of Australia
Australian Research Council
Australia Cancer Research Fund
Victorian State Government Operational Infrastructure Support (OIS) Grant
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
29 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献