Loss of function mutations and deletions in Wilms tumor 1 (WT1) gene are present in about 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 DNA damage response 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 γ-radiation in both T-cell acute lymphoblastic leukemia cell lines and patient xenografts. These results unveil an important role of (WT1) tumor suppressor gene in DNA damage response, and support a role for anti-XIAP targeted therapies in the treatment of (WT1)-mutant T-cell leukemia.

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

Bordin, Fulvio;Piovan, Erich;Minuzzo, Sonia;Bertorelle, Roberta;Pilotto, Giorgia;Basso, Giuseppe;Zanovello, Paola;Amadori, Alberto;Tosello, Valeria
2018

Abstract

Loss of function mutations and deletions in Wilms tumor 1 (WT1) gene are present in about 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 DNA damage response 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 γ-radiation in both T-cell acute lymphoblastic leukemia cell lines and patient xenografts. These results unveil an important role of (WT1) tumor suppressor gene in DNA damage response, and support a role for anti-XIAP targeted therapies in the treatment of (WT1)-mutant T-cell leukemia.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3251287
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