Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia
Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia
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DOI：
10.1038/s41375-022-01655-5
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发表时间：
2022-07-30
期刊：
影响因子：
11.4
通讯作者：
Sanda，Takaomi
中科院分区：
文献类型：
--
作者：
Ong，Jolynn Zu Lin;Yokomori，Rui;Sanda，Takaomi
成人T细胞白血病/淋巴瘤（ATL）是一种源自成熟T细胞的遗传复杂的血液系统恶性肿瘤。使用综合方法，我们先前确定了与ATL超增强子反复相关的基因。其中一个基因是wasTP73， atp53家族基因；然而，TP73及其超增强子在ATL发病机制中的作用和功能尚不清楚。我们的研究表明，TP73在ATL细胞的超增强子控制下高度激活，但在正常T细胞或其他血液系统恶性肿瘤中则不然。体外和体内ATL细胞维持需要全长TP73通过调控细胞增殖和DNA损伤反应通路。值得注意的是，在一部分携带超增强子的原发性ATL病例中观察到tp73外显子2-3的反复缺失，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是在ATL细胞的细胞内状态下顺序获得的，这导致TP73的功能改变，从而赋予额外的克隆优势。
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 wasTP73, aTP53family 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 ofTP73exons 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 theTP73intragenic 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.