TY - JOUR AU - Fulvio Bordin, AU - Erich Piovan, AU - Elena Masiero, AU - Alberto Ambesi-Impiombato, AU - Sonia Minuzzo, AU - Roberta Bertorelle, AU - Valeria Sacchetto, AU - Giorgia Pilotto, AU - Giuseppe Basso, AU - Paola Zanovello, AU - Alberto Amadori, AU - Valeria Tosello, PY - 2018/01/31 Y2 - 2024/03/29 TI - WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia JF - Haematologica JA - haematol VL - 103 IS - 2 SE - Articles DO - 10.3324/haematol.2017.170431 UR - https://haematologica.org/article/view/8349 SP - 266-277 AB - 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 γ-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. ER -