The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

Abstract

Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect.

Chromatin proteins and modifications as drug targets

“…CD11b). The inhibition of LSD1 activity was not associated with a global increase in H3K4me2, however, some increase in H3K4me2 was observed on MLL--AF9 bound genes and genes involved in differentiation 61,62 . Taken together these studies provide proof--of--concept for LSD1 as a therapeutic target in leukaemia, however, the mechanism by which LSD1 contributes to leukaemia is not clear for several reasons.…”

“…3c) 63 , which is more specific and 100--fold more potent than TCP 61 . The inhibition of LSD1 in AML led to increased differentiation followed by apoptosis, and consistent with this an increase in expression of differentiation markers (e.g.…”

“…Nevertheless, the recent demonstration that LSD1 is required for the development and maintenance of acute myeloid leukaemia (AML) has gained the most attention 61,62 . Specifically, both genetic and pharmacological data have been provided in vitro and in animal models showing that LSD1 is required to sustain the expression of genes induced by the MLL--AF9 oncoprotein and therefore the maintenance of the leukaemia stem cells (LSCs) 61 .…”

“…Specifically, both genetic and pharmacological data have been provided in vitro and in animal models showing that LSD1 is required to sustain the expression of genes induced by the MLL--AF9 oncoprotein and therefore the maintenance of the leukaemia stem cells (LSCs) 61 . The pharmacological results included the use of the general monooxidase inhibitor tranylcypromine (TCP) 62 ,…”

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

“…It is frequently overexpressed in NSCLC and promotes proliferation and invasion. 15 Again, the efficacy of LSD1 inhibition is deduced from its success in hematology: LSD1 inhibition was shown to remove the differentiation block in AML cells 16 and re-sensitize AML cells to all-trans retinoic acid (ATRA). 17 The first compound clinically used as an LSD1 inhibitor is tranylcypromine, a monoamine oxidase inhibitor approved more than 50 y ago for treatment-refractory depression.…”