Inhibition of the LSD1 (KDM1A) Demethylase Reactivates the All-Trans-Retinoic Acid Differentiation Pathway in Acute Myeloid Leukemia

Nat Med. 2012 Mar 11;18(4):605-11. doi: 10.1038/nm.2661.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • CD11b Antigen / metabolism
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Models, Animal
  • Drug Interactions
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Histone Demethylases / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology*
  • Lysine / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Small Interfering / metabolism
  • Stem Cell Factor / metabolism
  • Time Factors
  • Transplants
  • Tranylcypromine / therapeutic use
  • Tretinoin / pharmacology
  • Tretinoin / therapeutic use*

Substances

  • Antigens, CD34
  • CD11b Antigen
  • Cytokines
  • Enzyme Inhibitors
  • RNA, Small Interfering
  • Stem Cell Factor
  • Tranylcypromine
  • Tretinoin
  • Histone Demethylases
  • KDM1A protein, human
  • Lysine

Associated data

  • GEO/GSE34672
  • GEO/GSE34726