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LYMPHOMA

Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia

Leukemia volume 36, pages 2293–2305 (2022)Cite this article

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Abstract

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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Fig. 1: TP73 is highly expressed in ATL.
Fig. 2: Core transcription factor binding site controlling TP73 expression.
Fig. 3: Requirement of full-length TP73 for cancer cell maintenance.
Fig. 4: Genetic deletions associated with the formation of TP73 super-enhancer in ATL.
Fig. 5: TP73 regulates cell proliferation and DNA damage response pathways.
Fig. 6: Deletion of exons 2–3 further enhances cell proliferation.

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Acknowledgements

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.

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  1. These authors contributed equally: Jolynn Zu Lin Ong, Rui Yokomori.

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of, Singapore, 117599, Singapore

    Jolynn Zu Lin Ong, Rui Yokomori, Regina Wan Ju Wong, Tze King Tan & Takaomi Sanda

  2. Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan

    Ryuzo Ueda

  3. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan

    Takashi Ishida

  4. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan

    Shinsuke Iida

  5. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore, Singapore

    Takaomi Sanda

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Contributions

JZLO and RWJW performed the experiments; RY and TKT conducted the bioinformatic analyses; RU, TI, and SI provided the primary samples; and JZLO and TS wrote the manuscript.

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Correspondence to Takaomi Sanda.

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RU reports receiving research funding from Kyowa Kirin, Chugai and Ono Pharmaceutical.

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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 36, 2293–2305 (2022). https://doi.org/10.1038/s41375-022-01655-5

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