title: Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia.
abstract: Elevated expression of the Zinc finger E-box binding homeobox transcription factor-2 (ZEB2) is correlated with poor prognosis and patient outcome in a variety of human cancer subtypes. Using a conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventional chemotherapy. Here, we identified the lysine-specific demethylase KDM1A as a novel interaction partner of ZEB2 and demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival. Therefore, targeting the ZEB2 protein complex through direct disruption of the ZEB2-KDM1A interaction or pharmacological inhibition of the KDM1A demethylase activity itself could serve as a novel therapeutic strategy for this aggressive subtype of human leukemia and possibly other ZEB2-driven malignancies.
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.|Molecular and Cellular Oncology Laboratory, VIB Inflammation Research Center, Ghent, Belgium.|Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent, Ghent, Belgium.|Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.affiliation: Cancer Research Institute Ghent, Ghent, Belgium.|Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Peirs
authors.affiliation: Cancer Research Institute Ghent, Ghent, Belgium.|Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Van Loocke
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Jueqiong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.|Biochemistry and Physiology Laboratory, Department of Biological Applications, Radio-Isotopes Applications Division, Nuclear Research Centre, Egyptian Atomic Energy Authority, Abu-Zabal, Egypt.
authors.forename: Mina
authors.initials: M
authors.lastname: Takawy
authors.affiliation: Cancer Research Institute Ghent, Ghent, Belgium.|Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Matthijssens
authors.affiliation: Stem Cell Research Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Sonderegger
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Katharina
authors.initials: K
authors.lastname: Haigh
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Thao
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Molecular and Cellular Oncology Laboratory, VIB Inflammation Research Center, Ghent, Belgium.|Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent, Ghent, Belgium.
authors.forename: Niels
authors.initials: N
authors.lastname: Vandamme
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Magdaline
authors.initials: M
authors.lastname: Costa
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Carmichael
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium; and.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Nieuwerburgh
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium; and.
authors.forename: Dieter
authors.initials: D
authors.lastname: Deforce
authors.affiliation: Monash Biomedical Proteomics Facility, Monash University, Melbourne, VIC, Australia.
authors.forename: Oded
authors.initials: O
authors.lastname: Kleifeld
authors.affiliation: Stem Cell Research Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Curtis
authors.affiliation: Molecular and Cellular Oncology Laboratory, VIB Inflammation Research Center, Ghent, Belgium.|Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.affiliation: Cancer Research Institute Ghent, Ghent, Belgium.|Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps / Q000187:drug effects; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D001565:Benzoates; D003521:Cyclopropanes; C000602008:GSK2879552; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D056466:Histone Demethylases; C495195:KDM1A protein, human