Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

LYMPHOMA

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

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.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Waldmann TA. Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma. Oncogene. 2007;26:3699–703.

    PubMed  Article  CAS  Google Scholar 

  2. Matsuoka M, Jeang K-T. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007;7:270–80.

    PubMed  Article  CAS  Google Scholar 

  3. Ishitsuka K, Tamura K. Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol. 2014;15:517–26.

    Article  CAS  Google Scholar 

  4. Bangham CR, Ratner L. How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)? Curr Opin Virol. 2015;14:93–100.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. Watanabe T. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood. 2017;129:1071–81.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. Wong RWJ, Ngoc PCT, Leong WZ, Yam AWY, Zhang T, Asamitsu K, et al. Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia. Blood, J Am Soc Hematol. 2017;130:2326–38.

    CAS  Google Scholar 

  7. Wong RWJ, Tan TK, Amanda S, Ngoc PCT, Leong WZ, Tan SH, et al. Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma. Blood. 2020;135:934–47.

    PubMed  Article  Google Scholar 

  8. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J-I, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47:1304–15.

    PubMed  Article  CAS  Google Scholar 

  9. Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga J-I, et al. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood. 2022;139:967–82.

    PubMed  Article  CAS  Google Scholar 

  10. Yang A, McKeon F. P63 and P73: P53 mimics, menaces and more. Nat Rev Mol cell Biol. 2000;1:199–207.

    PubMed  Article  CAS  Google Scholar 

  11. Melino G, De Laurenzi V, Vousden KH. p73: Friend or foe in tumorigenesis. Nat Rev Cancer. 2002;2:605–15.

    PubMed  Article  CAS  Google Scholar 

  12. Gong J, Costanzo A, Yang H-Q, Melino G, Kaelin WG, Levrero M, et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature. 1999;399:806–9.

    PubMed  Article  CAS  Google Scholar 

  13. Ng S-W, Yiu GK, Liu Y, Huang L-W, Palnati M, Jun SH, et al. Analysis of p73 in human borderline and invasive ovarian tumor. Oncogene. 2000;19:1885–90.

    PubMed  Article  CAS  Google Scholar 

  14. O’nions J, Brooks L, Sullivan A, Bell A, Dunne B, Rozycka M, et al. p73 is over-expressed in vulval cancer principally as the δ 2 isoform. Br J Cancer. 2001;85:1551–6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. Zaika AI, Kovalev S, Marchenko ND, Moll UM. Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res. 1999;59:3257–63.

    PubMed  CAS  Google Scholar 

  16. Grob T, Novak U, Maisse C, Barcaroli D, Lüthi A, Pirnia F, et al. Human ΔNp73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ. 2001;8:1213–23.

    PubMed  Article  CAS  Google Scholar 

  17. Casciano I, Mazzocco K, Boni L, Pagnan G, Banelli B, Allemanni G, et al. Expression of ΔNp73 is a molecular marker for adverse outcome in neuroblastoma patients. Cell Death Differ. 2002;9:246–51.

    PubMed  Article  CAS  Google Scholar 

  18. Concin N, Becker K, Slade N, Erster S, Mueller-Holzner E, Ulmer H, et al. Transdominant ΔTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo. Cancer Res. 2004;64:2449–60.

    PubMed  Article  CAS  Google Scholar 

  19. Stiewe T, Tuve S, Peter M, Tannapfel A, Elmaagacli AH, Pützer BM. Quantitative TP73 transcript analysis in hepatocellular carcinomas. Clin Cancer Res. 2004;10:626–33.

    PubMed  Article  CAS  Google Scholar 

  20. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014;511:616–20.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 2002;416:560–4.

    PubMed  Article  CAS  Google Scholar 

  22. Zaika E, Wei J, Yin D, Andl C, Moll U, El‐Rifai W, et al. p73 protein regulates DNA damage repair. FASEB J. 2011;25:4406–14.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. Agami R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73α and their collaboration to induce apoptosis. Nature. 1999;399:809–13.

    PubMed  Article  CAS  Google Scholar 

  24. Nakagawa T, Takahashi M, Ozaki T, Watanabe K-I, Todo S, Mizuguchi H, et al. Autoinhibitory regulation of p73 by ΔNp73 to modulate cell survival and death through a p73-specific target element within the Δ Np73 promoter. Mol Cell Biol. 2002;22:2575–85.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Kinner A, Wu W, Staudt C, Iliakis G. γ-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res. 2008;36:5678–94.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, et al. γH2AX and cancer. Nat Rev Cancer. 2008;8:957–67.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Grassmann R, Aboud M, Jeang K-T. Molecular mechanisms of cellular transformation by HTLV-1 tax. Oncogene. 2005;24:5976–85.

    PubMed  Article  CAS  Google Scholar 

  28. Janssens S, Tinel A, Lippens S, Tschopp J. PIDD mediates NF-κB activation in response to DNA damage. Cell. 2005;123:1079–92.

    PubMed  Article  CAS  Google Scholar 

  29. Nakayama T, Hieshima K, Arao T, Jin Z, Nagakubo D, Shirakawa A, et al. Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. Oncogene. 2008;27:3221–32.

    PubMed  Article  CAS  Google Scholar 

  30. Nakagawa M, Shaffer AL, Ceribelli M, Zhang M, Wright G, Huang DW, et al. Targeting the HTLV-I-regulated BATF3/IRF4 transcriptional network in adult T cell leukemia/lymphoma. Cancer Cell. 2018;34:286–297.e210.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000;404:99–103.

    PubMed  Article  CAS  Google Scholar 

  32. Ikawa S, Nakagawara A, Ikawa Y. p53 family genes: structural comparison, expression and mutation. Cell Death Differ. 1999;6:1154–61.

    PubMed  Article  CAS  Google Scholar 

  33. Yang A, Kaghad M, Caput D, McKeon F. On the shoulders of giants: p63, p73 and the rise of p53. TRENDS Genet. 2002;18:90–95.

    PubMed  Article  Google Scholar 

  34. George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Kamada N, Sakurai M, Miyamoto K, Sanada I, Sadamori N, Fukuhara S, et al. Chromosome abnormalities in adult T-cell leukemia/lymphoma: a karyotype review committee report. Cancer Res. 1992;52:1481–93.

    PubMed  CAS  Google Scholar 

  37. Tsukasaki K, Krebs J, Nagai K, Tomonaga M, Koeffler HP, Bartram CR, et al. Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course. Blood. 2001;97:3875–81.

    PubMed  Article  CAS  Google Scholar 

  38. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153:307–19.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155:934–47.

    PubMed  Article  CAS  Google Scholar 

  40. Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M. t (8; 21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci USA. 1991;88:10431–4.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Ng CE, Yokomizo T, Yamashita N, Cirovic B, Jin H, Wen Z, et al. A Runx1 intronic enhancer marks hemogenic endothelial cells and hematopoietic stem cells. Stem Cells. 2010;28:1869–81.

    PubMed  Article  CAS  Google Scholar 

  42. Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature. 2009;457:887–91.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Hiebert SW, Sun W, Davis JN, Golub T, Shurtleff S, Buijs A, et al. The t (12; 21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol. 1996;16:1349–55.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Takaomi Sanda.

Ethics declarations

Competing interests

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41375-022-01655-5

Search

Quick links