title: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia.
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.
authors.affiliation: Division of Molecular Pathology, Institute of Cancer Research, Sutton, UK.
authors.forename: Tino
authors.initials: T
authors.lastname: Schenk
authors.forename: Weihsu Claire
authors.initials: WC
authors.lastname: Chen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Göllner
authors.forename: Louise
authors.initials: L
authors.lastname: Howell
authors.forename: Liqing
authors.initials: L
authors.lastname: Jin
authors.forename: Katja
authors.initials: K
authors.lastname: Hebestreit
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.forename: Andreea C
authors.initials: AC
authors.lastname: Popescu
authors.forename: Alan
authors.initials: A
authors.lastname: Burnett
authors.forename: Ken
authors.initials: K
authors.lastname: Mills
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Laurence
authors.initials: L
authors.lastname: Marton
authors.forename: Patrick
authors.initials: P
authors.lastname: Woster
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034741:RNA, Small Interfering / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D013997:Time Factors; D019737:Transplants; D014191:Tranylcypromine / Q000627:therapeutic use; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018952:Antigens, CD34; D039481:CD11b Antigen; D016207:Cytokines; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D019089:Stem Cell Factor; D014191:Tranylcypromine; D014212:Tretinoin; D056466:Histone Demethylases; C495195:KDM1A protein, human; D008239:Lysine