Adult T-cell leukemia/lymphoma (ATL) is a genetically complex hematological malignancy derived from mature T cells. Using an integrative approach, we previously identified genes recurrently associated with super-enhancers in ATL. One of those genes was TP73, a TP53 family gene; however, the roles and function of TP73 and its super-enhancer in ATL pathogenesis are poorly understood. Our study demonstrates that TP73 is highly activated under the control of a super-enhancer in ATL cells but not in normal T cells or other hematological malignancies examined. Full-length TP73 is required for ATL cell maintenance in vitro and in vivo via the regulation of cell proliferation and DNA damage response pathways. Notably, recurrent deletions of TP73 exons 2–3 were observed in a fraction of primary ATL cases that harbored the super-enhancer, while induction of this deletion in cell lines further increased proliferation and mutational burden. Our study suggests that formation of the TP73 intragenic super-enhancer and genetic deletion are likely sequentially acquired in relation to intracellular state of ATL cells, which leads to functional alteration of TP73 that confers additional clonal advantage.

成人 T 细胞白血病/淋巴瘤 (ATL) 是一种遗传复杂的血液恶性肿瘤，来源于成熟的 T 细胞。我们以前使用综合方法确定了与 ATL 中的超级增强子反复相关的基因。其中一个基因是TP73，一个TP53家族基因；然而，人们对 TP73 及其超级增强子在 ATL 发病机制中的作用和功能知之甚少。我们的研究表明，TP73 在 ATL 细胞中的超增强子控制下高度激活，但在正常 T 细胞或其他检查的血液恶性肿瘤中没有。通过调节细胞增殖和 DNA 损伤反应途径，ATL 细胞在体外和体内的维持需要全长 TP73。值得注意的是，TP73的反复缺失在一部分含有超级增强子的原发性 ATL 病例中观察到外显子 2-3，而在细胞系中诱导这种缺失进一步增加了增殖和突变负担。我们的研究表明，TP73基因内超增强子的形成和基因缺失可能与 ATL 细胞的细胞内状态相关，从而导致 TP73 的功能改变，从而赋予额外的克隆优势。