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 and Zelent, Arthur (2012) Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature medicine, 18 (4). pp. 605-11. ISSN 1546-170X
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Abstract
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 (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 γ (with interleukin-2 (IL-2) receptor γ 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.
| Item Type: | Article |
|---|---|
| Depositing User: | Kevin Petrie |
| URI: | https://sure.sunderland.ac.uk/id/eprint/12434 |
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