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Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia


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 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.

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Figure 1: LSD1 inhibitors potentiate ATRA-induced differentiation of AML cells.
Figure 2: Treatment with ATRA and TCP together diminishes the engraftment of primary AML samples.
Figure 3: Treatment with ATRA plus TCP enhances the expression of a subset of genes associated with the myeloid differentiation pathway.
Figure 4: Gene-specific increases in H3K4me2 induced by treatment with ATRA plus TCP correlate with the upregulation of myeloid-differentiation–associated gene expression.

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T.S., L.H., K.P. and A.Z. were supported by a Specialist Programme Grant from Leukaemia and Lymphoma Research. T.S., L.H., K.P. and A.Z. were also supported in part by the Samuel Waxman Cancer Research Foundation. S.G. and C.M.-T. were supported by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) and the Deutsche Forschungsgemeinschaft (1328/6-1, 8-1 and 9-1). W.C.C., L.J., J.C.Y.W. and J.E.D. were supported by the Cancer Stem Cell Consortium with funding from the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-047) and through the Canadian Institute of Health Research (CSC-105367), as well as with funding from Canadian Institutes for Health Research (CIHR), the Canadian Cancer Society Research Institute, the Terry Fox Foundation; Genome Canada through the Ontario Genomics Institute; Ontario Institute for Cancer Research with funds from the province of Ontario; and a Canada Research Chair. W.C.C., L.J., J.C.Y.W. and J.E.D. were also funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed here do not necessarily reflect those of the OMOHLTC. R.A.C. Jr. was supported by a National Cancer Institute Grant (CA51085). The authors would like to thank D. Leongamornlert, L. Jasnos and S. Bashir for valuable discussions on the interpretation of the ChIP-Seq data and the statistical analyses. The authors would also like to thank M. Greaves for support and critical reading of the manuscript.

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Authors and Affiliations



T.S. performed cell drug treatments, ChIP-Seq, quantitative PCR, RNAi and western blotting; L.H. performed cell drug treatments, FACS, the superoxide assay, immunohistochemical staining and light microscopy; S.G. and C.M.-T. performed ChIP-Seq and primary AML sample drug treatments; W.C.C., L.J., A.C.P., J.C.Y.W. and J.E.D. performed in vivo treatments of AML in NOD-SCID and NSG mice; K.H., H.-U.K. and M.D. performed bioinformatic analyses of expression microarray and ChIP-Seq data; A.B., K.M. and M.D.M. isolated primary AML samples; P.W., L.M. and R.A.C. Jr. collaborated on the 2d LSD1 inhibitor; T.S., K.P. and A.Z. designed the study and analyzed the data; K.P. and A.Z. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Arthur Zelent.

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Competing interests

L.M. was employed by Progen Pharmaceuticals. R.A.C. and P.W. have received funding from Progen Pharmaceuticals.

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Supplementary Figures 1–11, Supplementary Tables 1–3 and Supplementary Methods (PDF 4269 kb)

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Supplementary Data 2 (XLS 483 kb)

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Schenk, T., Chen, W., Göllner, S. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 18, 605–611 (2012).

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