Oral Presentation 28th Lorne Cancer Conference 2016

Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a. (#12)

Ben J Shields 1 , Jacob T Jackson 1 , Don Metcalf 1 , Wei Shi 1 , Qiutong Huang 1 , Alexandra Garnham 1 , Stephan Glaser 1 , Dominik Beck 2 , John Pimanda 2 , Clifford W Bogue 3 , Gordon Smyth 1 , Warren Alexander 1 , Matthew P McCormack 1
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
  3. Yale University, New Haven, CT , USA
Acute myeloid leukemia is frequently caused by chromosomal translocations at the MLL locus, which link MLL to a vast number of fusion partners. In these cases, MLL fusion proteins cause expression of an aberrant transcriptional program driven by HOXA genes, in addition to aberrant epigenetic modifications.

Unlike HOXA genes, the role of non-clustered homeobox gene family members in AML leukemogenesis has not been extensively studied. We have studied the role of the Hematopoietically-expressed Homeobox gene in this process. We find that Hhex is overexpressed in human AML and is essential for the initiation and propagation of MLL-ENL induced AML in mouse models, 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 recruits the Polycomb Repressive Complex 2 (PRC2) to enable H3K27Me3-mediated epigenetic repression. Thus, Hhex is a novel therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.