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- Title
Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia.
- Authors
Schenk, Tino; Chen, Weihsu Claire; Göllner, Stefanie; Howell, Louise; Jin, Liqing; Hebestreit, Katja; Klein, Hans-Ulrich; Popescu, Andreea C; Burnett, Alan; Mills, Ken; Casero, Robert A; Marton, Laurence; Woster, Patrick; Minden, Mark D; Dugas, Martin; Wang, Jean C Y; Dick, John E; Müller-Tidow, Carsten; Petrie, Kevin; Zelent, Arthur
- Abstract
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 (H3K4me2) across the genome, but it did increase H3K4me2 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 ? (with interleukin-2 (IL-2) receptor ? 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.
- Subjects
ACUTE promyelocytic leukemia; DEMETHYLASE; TRETINOIN; TRANYLCYPROMINE; SEVERE combined immunodeficiency
- Publication
Nature Medicine, 2012, Vol 18, Issue 4, p605
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.2661