The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia Journal Article
| Authors: | Van Der Meulen, J.; Sanghvi, V.; Mavrakis, K.; Durinck, K.; Fang, F.; Matthijssens, F.; Rondou, P.; Rosen, M.; Pieters, T.; Vandenberghe, P.; Delabesse, E.; Lammens, T.; De Moerloose, B.; Menten, B.; Van Roy, N.; Verhasselt, B.; Poppe, B.; Benoit, Y.; Taghon, T.; Melnick, A. M.; Speleman, F.; Wendel, H. G.; Van Vlierberghe, P. |
| Article 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. |
| Keywords: | clinical article; controlled study; human tissue; unclassified drug; human cell; single nucleotide polymorphism; somatic mutation; histopathology; nonhuman; cancer patient; t lymphocyte; animal cell; chromosome; mouse; enzyme inhibition; gene expression; gene function; in vivo study; in vitro study; acute lymphoblastic leukemia; epigenetics; multicenter study; x chromosome inactivation; tumor suppressor protein; loss of function mutation; t cell leukemia; histone demethylase; histone methylation; lymphoblast; human; female; article; ubiquitously transcribed x protein; t cell acute lymphoblastic leukemia |
| Journal Title: | Blood |
| Volume: | 125 |
| Issue: | 1 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2015-01-01 |
| Start Page: | 13 |
| End Page: | 21 |
| Language: | English |
| DOI: | 10.1182/blood-2014-05-577270 |
| PROVIDER: | scopus |
| PUBMED: | 25320243 |
| PMCID: | PMC4347284 |
| DOI/URL: | |
| Notes: | Export Date: 2 February 2015 -- Source: Scopus |
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