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

Fulvio Bordin, Erich Piovan, Elena Masiero, Alberto Ambesi-Impiombato, Sonia Minuzzo, Roberta Bertorelle, Valeria Sacchetto, Giorgia Pilotto, Giuseppe Basso, Paola Zanovello, Alberto Amadori, Valeria Tosello

Research output: Contribution to journalArticle

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,WT1mutations 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.WT1loss conferred resistance to DNA damaging agents and attenuated the transcriptional activation of important apoptotic regulators downstream of TP53 inTP53-competent MOLT4 T-leukemia cells but not inTP53-mutant T-cell acute lymphoblastic leukemia cell lines. Notably,WT1loss 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 theWT1tumor suppressor gene in the response to DNA damage, and support the view that anti-XIAP targeted therapies could have a role in the treatment ofWT1-mutant T-cell leukemia.

Original languageEnglish
Pages (from-to)266-277
Number of pages12
JournalHaematologica
Volume103
Issue number2
Early online dateNov 13 2017
DOIs
Publication statusPublished - Feb 2018

Keywords

  • Journal Article

Fingerprint Dive into the research topics of 'WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this