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

Tino Schenk, Weihsu Claire Chen, Stefanie Göllner, Louise Howell, Liqing Jin, Katja Hebestreit, Hans Ulrich Klein, Andreea C. Popescu, Alan Burnett, Ken Mills, Robert A. Casero, Laurence Marton, Patrick Woster, Mark D. Minden, Martin Dugas, Jean C.Y. Wang, John E. Dick, Carsten Müller-Tidow, Kevin Petrie, Arthur Zelent

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)605-611
Number of pages7
JournalNature medicine
Volume18
Issue number4
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Schenk, T., Chen, W. C., Göllner, S., Howell, L., Jin, L., Hebestreit, K., Klein, H. U., Popescu, A. C., Burnett, A., Mills, K., Casero, R. A., Marton, L., Woster, P., Minden, M. D., Dugas, M., Wang, J. C. Y., Dick, J. E., Müller-Tidow, C., Petrie, K., & Zelent, A. (2012). Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature medicine, 18(4), 605-611. https://doi.org/10.1038/nm.2661