title: The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that is mainly diagnosed in children and shows a skewed gender distribution toward males. In this study, we report somatic loss-of-function mutations in the X-linked histone H3K27me3 demethylase ubiquitously transcribed X (UTX) chromosome, in human T-ALL. Interestingly, UTX mutations were exclusively present in male T-ALL patients and allelic expression analysis revealed that UTX escapes X-inactivation in female T-ALL lymphoblasts and normal T cells. Notably, we demonstrate in vitro and in vivo that the H3K27me3 demethylase UTX functions as a bona fide tumor suppressor in T-ALL. Moreover, T-ALL driven by UTX inactivation exhibits collateral sensitivity to pharmacologic H3K27me3 inhibition. All together, our results show how a gender-specific and therapeutically relevant defect in balancing H3K27 methylation contributes to T-cell leukemogenesis.
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Joni
authors.initials: J
authors.lastname: Van der Meulen
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Viraj
authors.initials: V
authors.lastname: Sanghvi
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mavrakis
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Kaat
authors.initials: K
authors.lastname: Durinck
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Filip
authors.initials: F
authors.lastname: Matthijssens
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Monica
authors.initials: M
authors.lastname: Rosen
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium;
authors.forename: Tim
authors.initials: T
authors.lastname: Pieters
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium;
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: INSERM U563, Toulouse, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; and.
authors.forename: Tim
authors.initials: T
authors.lastname: Lammens
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; and.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Björn
authors.initials: B
authors.lastname: Menten
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Verhasselt
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000737:chemistry; D006801:Humans; D016130:Immunophenotyping; D007378:Interleukins / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012737:Sex Factors; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D006657:Histones; D007378:Interleukins; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; C111778:Utx protein, mouse