The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une déméthylase (UTX) exerce une fonction de suppresseur de tumeurs dans les leucémies lymphoblastiques aiguës T affectant des patients masculins
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 towards males. Here, we report somatic loss-of-function mutations in the X-linked histone H3K27me3 demethylase UTX 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 pharmacological H3K27me3 inhibition. All together, our results show how a gender-specific and therapeutically relevant defect in balancing H3K27 methylation contributes to T-cell leukemogenesis.