Journal
NATURE MEDICINE
Volume 18, Issue 4, Pages 605-611Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2661
Keywords
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Funding
- Leukaemia and Lymphoma Research
- Samuel Waxman Cancer Research Foundation
- Interdisziplinares Zentrum fur Klinische Forschung (IZKF)
- Deutsche Forschungsgemeinschaft [1328/6-1, 8-1, 9-1]
- Cancer Stem Cell Consortium
- Government of Canada
- Ontario Genomics Institute through the Canadian Institute of Health Research [OGI-047, CSC-105367]
- Canadian Institutes for Health Research (CIHR)
- Canadian Cancer Society Research Institute
- Terry Fox Foundation
- province of Ontario
- Canada Research Chair
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- National Cancer Institute [CA51085]
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Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15; 17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4(me2)) across the genome, but it did increase H3K4(me2) and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID gamma (with interleukin-2 (IL-2) receptor gamma chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.
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