Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università degli Studi di Padova, Italy.
U.O.C. Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.
Haematologica. 2018 Feb;103(2):266-277. doi: 10.3324/haematol.2017.170431. Epub 2017 Nov 23.
Loss-of-function mutations and deletions in Wilms tumor 1 () gene are present in approximately 10% of T-cell acute lymphoblastic leukemia. Clinically, 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. loss conferred resistance to DNA damaging agents and attenuated the transcriptional activation of important apoptotic regulators downstream of TP53 in -competent MOLT4 T-leukemia cells but not in -mutant T-cell acute lymphoblastic leukemia cell lines. Notably, 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 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 -mutant T-cell leukemia.
Wilms 瘤 1()基因的功能丧失突变和缺失约存在于 10%的 T 细胞急性淋巴细胞白血病中。临床上，突变在复发系列中富集，并与胸苷 T 细胞急性淋巴细胞白血病病例的无复发生存率降低相关。在这里，我们证明 WT1 在 T 细胞白血病对 DNA 损伤的反应中起关键作用。 缺失赋予了对 DNA 损伤剂的抗性，并减弱了 MOLT4 T 白血病细胞中 TP53 下游重要凋亡调节剂的转录激活，但在 -突变的 T 细胞急性淋巴细胞白血病细胞系中则不然。值得注意的是，缺失可显著影响 X 连锁凋亡抑制剂蛋白 XIAP 的表达，并且用 embelin（XIAP 抑制剂）进行遗传或化学抑制可显著恢复两种 T 细胞急性淋巴细胞白血病细胞系和患者来源异种移植物对 γ 辐射的敏感性。这些结果揭示了 肿瘤抑制基因在 DNA 损伤反应中的重要作用，并支持这样一种观点，即抗 XIAP 靶向治疗可能在治疗 -突变的 T 细胞白血病中发挥作用。
