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

Benjamin 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

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

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 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 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.

Original languageEnglish
Pages (from-to)78-91
Number of pages14
JournalGenes and Development
Volume30
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • Homeobox
  • Self-renewal
  • Transcription factor
  • Tumor suppressor

Cite this

Shields, Benjamin ; 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. / Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a. In: Genes and Development. 2016 ; Vol. 30, No. 1. pp. 78-91.
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author = "Benjamin Shields and Jackson, {Jacob T.} and Donald Metcalf and Wei Shi and Qiutong Huang and Garnham, {Alexandra L.} and Glaser, {Stefan P.} and Dominik Beck and Pimanda, {John E.} and Bogue, {Clifford W.} and Smyth, {Gordon K.} and Alexander, {Warren S.} and McCormack, {Matthew P.}",
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Shields, B, Jackson, JT, Metcalf, D, Shi, W, Huang, Q, Garnham, AL, Glaser, SP, Beck, D, Pimanda, JE, Bogue, CW, Smyth, GK, Alexander, WS & McCormack, MP 2016, 'Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a', Genes and Development, vol. 30, no. 1, pp. 78-91. https://doi.org/10.1101/gad.268425.115

Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a. / Shields, Benjamin; 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.

In: Genes and Development, Vol. 30, No. 1, 01.01.2016, p. 78-91.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jackson, Jacob T.

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AU - Shi, Wei

AU - Huang, Qiutong

AU - Garnham, Alexandra L.

AU - Glaser, Stefan P.

AU - Beck, Dominik

AU - Pimanda, John E.

AU - Bogue, Clifford W.

AU - Smyth, Gordon K.

AU - Alexander, Warren S.

AU - McCormack, Matthew P.

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N2 - 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 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 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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