ReferenceID 3559
WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia
Haematologica
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
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Record Fields
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- Reference Id
- 3559
- Evidence Id
- 20149
- Core Evidence Id
- 20149
- Source Reference Id
- 425
- Herb2 Reference Id
- HBREF000742
- Subject Paper Key
- HBIN025026_29170254
- Pubmed Id
- 29170254
- Doi
- 10.3324/haematol.2017.170431
- Paper Title
- WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia
- Paper 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 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.
- Journal
- Haematologica
- Publish Year
- 2018
- Experiment Subject
- Experiment Type
- Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia
- Bilingual Status
- semi_complete