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
GENES & DEVELOPMENT | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2016
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 ..View full abstract
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We thank Ian Majewski for reagents and helpful comments on the manuscript; Jason Corbin and Jasmin McManus for blood analysis; Waruni Abeysekera for aligning ChIP sequencing reads; Sandra Mifsud, Ladina DiRago, Chayanica Nasa, William Stanley, and Stephen Wilcox for technical assistance; Walter and Eliza Hall Institute Bioservices for mouse husbandry; and the Walter and Eliza Hall Institute Flow Cytometry Facility. We also thank Tobias Herold (Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians-Universitat, Munich, Germany) and Peter J.M. Valk (Department of Hematology and Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands) for providing clinical data. This work was supported by a Program grant (101664 to W.S.A.), Project grants (628386 and 1003391 to M.P.M.), a fellowship (1058344 to W.S.A.), the Independent Research Institutes Infrastructure Support (IRIIS) Scheme from the Australian Government's National Health and Medical Research Council (NHMRC), grants-in-aid from the Cancer Council of Victoria and the Leukemia Foundation of Australia (M.P.M. and S.P.G.), a Future Fellowship from the Australian Research Council (M.P.M.), the Australia Cancer Research Fund (W.S.A.), and a Victorian State Government Operational Infrastructure Support (OIS) Grant.