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.
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We thank Nature Publishing Group Language Editing for editing the manuscript. We thank the members of the Sanda laboratory for discussions and critical reviews. We acknowledge support from the Yong Loo Lin School of Medicine BSL-3 Core Facility, National University of Singapore, National University Health System, and from the Singapore Ministry of Health, National Medical Research Council, Center Grant ‘MINE’, Research Core #4 (NMRC/CG/013/2013). This research is supported by the National Medical Research Council of the Singapore Ministry of Health (NMRC/CIRG/1491/2018 and OFLCG18May-0028: TS); the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative (TS); Japan Society for the Promotion of Science, KAKENHI (18K19960: TS and SI); and the Japan Agency for Medical Research and Development (no.19ae0101074s0401: RU). Illustrations were created with Biorender.
RU reports receiving research funding from Kyowa Kirin, Chugai and Ono Pharmaceutical.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Ong, J.Z.L., Yokomori, R., Wong, R.W.J. et al. Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia. Leukemia (2022). https://doi.org/10.1038/s41375-022-01655-5