The methyltransferase G9a regulates HoxA9-dependent transcription in AML
- Bernhard Lehnertz1,2,
- Caroline Pabst2,
- Le Su1,
- Michelle Miller3,
- Feng Liu4,
- Lin Yi1,
- Regan Zhang1,
- Jana Krosl2,
- Eric Yung2,
- Jeanette Kirschner1,
- Patty Rosten3,
- T. Michael Underhill1,
- Jian Jin4,
- Josée Hébert2,5,
- Guy Sauvageau2,
- R. Keith Humphries3 and
- Fabio M. Rossi1,6
- 1University of British Columbia, Biomedical Research Centre, Vancouver, British Columbia V6T 1Z3, Canada;
- 2University of Montreal, Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada;
- 3Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
- 4University of North Carolina at Chapel Hill, Center for Integrative Chemical Biology and Drug Discovery, Chapel Hill, North Carolina 27599, USA;
- 5Leukemia Cell Bank of Quebec (BCLQ), Maisonneuve-Rosemont Hospital, Montréal, Quebec H1T 2M4, Canada
Abstract
Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.
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Footnotes
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↵6 Corresponding author
E-mail fabio{at}brc.ubc.ca
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.236794.113.
- Received September 25, 2013.
- Accepted January 6, 2014.
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