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Blood. 2015 Jan 1;125(1):13-21. doi: 10.1182/blood-2014-05-577270. Epub 2014 Oct 15.

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

Author information

1
Center for Medical Genetics, Ghent University, Ghent, Belgium;
2
Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY;
3
Department of Medicine, Weill Cornell Medical College, New York, NY;
4
Center for Medical Genetics, Ghent University, Ghent, Belgium; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium;
5
Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium;
6
INSERM U563, Toulouse, France;
7
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; and.
8
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.

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.

PMID:
25320243
PMCID:
PMC4347284
DOI:
10.1182/blood-2014-05-577270
[Indexed for MEDLINE]
Free PMC Article

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