WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia
| Title: | WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia |
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| Authors: | 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 |
| Source: | Haematologica, Vol 103, Iss 2 (2018) |
| Publisher Information: | Ferrata Storti Foundation, 2018. |
| Publication Year: | 2018 |
| Collection: | LCC:Diseases of the blood and blood-forming organs |
| Subject Terms: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/8349; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2017.170431 |
| Access URL: | https://doaj.org/article/30bca272e61a416b92e1683391eb37d0 |
| Accession Number: | edsdoj.30bca272e61a416b92e1683391eb37d0 |
| Database: | Directory of Open Access Journals |
| ISSN: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2017.170431 |
| Published in: | Haematologica |
| Language: | English |