title: Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a.
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.
authors.affiliation: 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;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Shields
authors.affiliation: Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Jackson
authors.affiliation: 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;
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: 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;
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Qiutong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia;
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Garnham
authors.affiliation: 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;
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.affiliation: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia;
authors.forename: Dominik
authors.initials: D
authors.lastname: Beck
authors.affiliation: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia;
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut 06510, USA;
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Bogue
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia; Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3050, Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: 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;
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: 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;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: McCormack
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C513080:Hhex protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2
keywords: acute myeloid leukemia; homeobox; self-renewal; transcription factor; tumor suppressor