TY - JOUR
T1 - The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia
AU - Van Der Meulen, Joni
AU - Sanghvi, Viraj
AU - Mavrakis, Konstantinos
AU - Durinck, Kaat
AU - Fang, Fang
AU - Matthijssens, Filip
AU - Rondou, Pieter
AU - Rosen, Monica
AU - Pieters, Tim
AU - Vandenberghe, Peter
AU - Delabesse, Eric
AU - Lammens, Tim
AU - De Moerloose, Barbara
AU - Menten, Björn
AU - Van Roy, Nadine
AU - Verhasselt, Bruno
AU - Poppe, Bruce
AU - Benoit, Yves
AU - Taghon, Tom
AU - Melnick, Ari M.
AU - Speleman, Frank
AU - Wendel, Hans Guido
AU - Van Vlierberghe, Pieter
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2014-05-577270
DO - 10.1182/blood-2014-05-577270
M3 - Article
C2 - 25320243
AN - SCOPUS:84920580721
VL - 125
SP - 13
EP - 21
JO - Blood
JF - Blood
SN - 0006-4971
IS - 1
ER -