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Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a.
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.
Affiliation
  • Shields BJ; 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;
  • Jackson JT; Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
  • Metcalf D; 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;
  • Shi W; 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;
  • Huang Q; Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
  • Garnham AL; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia;
  • Glaser SP; 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;
  • Beck D; Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia;
  • Pimanda JE; Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia;
  • Bogue CW; Yale University School of Medicine, New Haven, Connecticut 06510, USA;
  • Smyth GK; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia; Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3050, Australia.
  • Alexander WS; 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;
  • McCormack MP; 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;
Genes Dev ; 30(1): 78-91, 2016 Jan 01.
Article in En | MEDLINE | ID: mdl-26728554
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Leukemia, Myeloid, Acute / Homeodomain Proteins / Cyclin-Dependent Kinase Inhibitor p16 / Epigenesis, Genetic / Polycomb Repressive Complex 2 Limits: Animals / Humans Language: En Journal: Genes Dev Journal subject: BIOLOGIA MOLECULAR Year: 2016 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Leukemia, Myeloid, Acute / Homeodomain Proteins / Cyclin-Dependent Kinase Inhibitor p16 / Epigenesis, Genetic / Polycomb Repressive Complex 2 Limits: Animals / Humans Language: En Journal: Genes Dev Journal subject: BIOLOGIA MOLECULAR Year: 2016 Document type: Article