TitleThe H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsVan der Meulen, Joni, Sanghvi Viraj, Mavrakis Konstantinos, Durinck Kaat, Fang Fang, Matthijssens Filip, Rondou Pieter, Rosen Monica, Pieters Tim, Vandenberghe Peter, Delabesse Eric, Lammens Tim, De Moerloose Barbara, Menten Björn, Van Roy Nadine, Verhasselt Bruno, Poppe Bruce, Benoit Yves, Taghon Tom, Melnick Ari M., Speleman Frank, Wendel Hans-Guido, and Van Vlierberghe Pieter
Date Published2015 Jan 01
KeywordsAlleles, Animals, Cell Line, Tumor, Cell Survival, Cohort Studies, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Leukemic, Histone Demethylases, Histones, Humans, Immunophenotyping, Interleukins, Male, Mice, Mutation, Nuclear Proteins, Polymorphism, Single Nucleotide, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Real-Time Polymerase Chain Reaction, Sex Factors, T-Lymphocytes

<p>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.</p>

Alternate JournalBlood
PubMed ID25320243
PubMed Central IDPMC4347284
Grant ListR01 CA142798 / CA / NCI NIH HHS / United States
U01 CA105492 / CA / NCI NIH HHS / United States
U01CA105492-08 / CA / NCI NIH HHS / United States
R01-CA142798-01 / CA / NCI NIH HHS / United States