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WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia.


ABSTRACT: Loss-of-function mutations and deletions in Wilms tumor 1 (WT1) gene are present in approximately 10% of T-cell acute lymphoblastic leukemia. Clinically, WT1 mutations are enriched in relapsed series and are associated to inferior relapse-free survival in thymic T-cell acute lymphoblastic leukemia cases. Here we demonstrate that WT1 plays a critical role in the response to DNA damage in T-cell leukemia. WT1 loss conferred resistance to DNA damaging agents and attenuated the transcriptional activation of important apoptotic regulators downstream of TP53 in TP53-competent MOLT4 T-leukemia cells but not in TP53-mutant T-cell acute lymphoblastic leukemia cell lines. Notably, WT1 loss positively affected the expression of the X-linked inhibitor of apoptosis protein, XIAP, and genetic or chemical inhibition with embelin (a XIAP inhibitor) significantly restored sensitivity to ?-radiation in both T-cell acute lymphoblastic leukemia cell lines and patient-derived xenografts. These results reveal an important role for the WT1 tumor suppressor gene in the response to DNA damage, and support the view that anti-XIAP targeted therapies could have a role in the treatment of WT1-mutant T-cell leukemia.

SUBMITTER: Bordin F 

PROVIDER: S-EPMC5792271 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Loss-of-function mutations and deletions in Wilms tumor 1 (<i>WT1</i>) gene are present in approximately 10% of T-cell acute lymphoblastic leukemia. Clinically, <i>WT1</i> mutations are enriched in relapsed series and are associated to inferior relapse-free survival in thymic T-cell acute lymphoblastic leukemia cases. Here we demonstrate that WT1 plays a critical role in the response to DNA damage in T-cell leukemia. <i>WT1</i> loss conferred resistance to DNA damaging agents and attenuated the  ...[more]

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