The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia

Joni Van Der Meulen, Viraj Sanghvi, Konstantinos Mavrakis, Kaat Durinck, Fang Fang, Filip Matthijssens, Pieter Rondou, Monica Rosen, Tim Pieters, Peter Vandenberghe, Eric Delabesse, Tim Lammens, Barbara De Moerloose, Björn Menten, Nadine Van Roy, Bruno Verhasselt, Bruce Poppe, Yves Benoit, Tom Taghon, Ari M. MelnickFrank Speleman, Hans Guido Wendel, Pieter Van Vlierberghe

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13-21
Number of pages9
JournalBlood
Volume125
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint

Dive into the research topics of 'The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this