Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a

Benjamin J Shields; Jacob T Jackson; Donald Metcalf; Wei Shi; Qiutong Huang; Alexandra L Garnham; Stefan P Glaser; Dominik Beck; John E Pimanda; Clifford W Bogue; Gordon K Smyth; Warren S Alexander; Matthew P McCormack

doi:10.1101/gad.268425.115

Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a

Genes Dev. 2016 Jan 1;30(1):78-91. doi: 10.1101/gad.268425.115.

Affiliations

¹ Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia;
² Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
³ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia; Computing and Information Systems, University of Melbourne, Parkville, Victoria 3050, Australia;
⁴ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia;
⁵ Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia;
⁶ Yale University School of Medicine, New Haven, Connecticut 06510, USA;
⁷ Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia; Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3050, Australia.

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 p16(INK4a) and p19(ARF), 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.

Keywords: acute myeloid leukemia; homeobox; self-renewal; transcription factor; tumor suppressor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
Epigenesis, Genetic*
Gene Deletion
Gene Expression Regulation, Neoplastic
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / physiopathology*
Mice
Mice, Inbred C57BL
Polycomb Repressive Complex 2 / genetics*
Polycomb Repressive Complex 2 / metabolism*
Protein Binding
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Cyclin-Dependent Kinase Inhibitor p16
Hhex protein, mouse
Homeodomain Proteins
Transcription Factors
Polycomb Repressive Complex 2