title: 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.
authors.affiliation: Cancer Research UK Leukaemia Biology Laboratory, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
authors.forename: William J
authors.initials: WJ
authors.lastname: Harris
authors.forename: Xu
authors.initials: X
authors.lastname: Huang
authors.forename: James T
authors.initials: JT
authors.lastname: Lynch
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Spencer
authors.forename: James R
authors.initials: JR
authors.lastname: Hitchin
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.forename: Filippo
authors.initials: F
authors.lastname: Ciceri
authors.forename: Julian G
authors.initials: JG
authors.lastname: Blaser
authors.forename: Brigit F
authors.initials: BF
authors.lastname: Greystoke
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Crispin J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
authors.forename: Tim C P
authors.initials: TC
authors.lastname: Somervaille
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056466:Histone Demethylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000502:physiology*
chemical_list: C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating