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

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Wilms Tumor
T-Cell Leukemia
DNA Damage
X-Linked Inhibitor of Apoptosis Protein
Wilms' Tumor Genes
Suppressor Genes
Cell Line
Sequence Deletion
Radiation Tolerance
Heterografts
Transcriptional Activation
Recurrence
Survival
DNA
Therapeutics

Keywords

  • Journal Article

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WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia. / Bordin, Fulvio; Piovan, Erich; Masiero, Elena; Ambesi-Impiombato, Alberto; Minuzzo, Sonia; Bertorelle, Roberta; Sacchetto, Valeria; Pilotto, Giorgia; Basso, Giuseppe; Zanovello, Paola; Amadori, Alberto; Tosello, Valeria.

In: Haematologica, Vol. 103, No. 2, 02.2018, p. 266-277.

Research output: Contribution to journalArticle

Bordin, Fulvio ; Piovan, Erich ; Masiero, Elena ; Ambesi-Impiombato, Alberto ; Minuzzo, Sonia ; Bertorelle, Roberta ; Sacchetto, Valeria ; Pilotto, Giorgia ; Basso, Giuseppe ; Zanovello, Paola ; Amadori, Alberto ; Tosello, Valeria. / WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia. In: Haematologica. 2018 ; Vol. 103, No. 2. pp. 266-277.
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AU - Zanovello, Paola

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