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.

  • Perspective
  • Published:

LYMPHOMA

Silencing GNAS enhances HDAC3i efficacy in CREBBP wild type B cell lymphoma

Leukemia (2024)Cite this article

Subjects

Abstract

The genetic era has opened the opportunity of using personalized therapeutic approaches, in part based on targeting genes with somatic mutations. For example, lymphomas harboring the highly recurrent CREBBP mutation show dependency on HDAC3, thus selective inhibition of HDAC3 reversed the epigenetic effects of CREBBP mutation, halted lymphoma growth, and induced MHC class II expression, enabling the T-cells to recognize and kill lymphoma cells. However, CREBBP wild type (WT) cells are less sensitive to this approach. In this issue of Leukemia, He et al. have executed a genome-wide CRISPR screening that identified GNAS as a target to maximize the therapeutic activity of HDAC3 inhibition in CREBBP WT lymphoma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: GNAS knockout potentiates HDAC3 inhibition through immune and viral mimicry-related responses in lymphoma.

Similar content being viewed by others

References

  1. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mondello P, Tadros S, Teater M, Fontan L, Chang AY, Jain N, et al. Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma. Cancer Discov. 2020;10:440–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, et al. Genetics of follicular lymphoma transformation. Cell Rep. 2014;6:130–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schroers-Martin JG, Soo J, Brisou G, Scherer F, Kurtz DM, Sworder BJ, et al. Tracing founder mutations in circulating and tissue-resident follicular lymphoma precursors. Cancer Discov 2023;13:1310–23.

  7. Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci. 2015;112:E1116–E1125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mondello P, Fama A, Larson MC, Feldman AL, Villasboas JC, Yang ZZ, et al. Lack of intrafollicular memory CD4 + T cells is predictive of early clinical failure in newly diagnosed follicular lymphoma. Blood Cancer J. 2021;11:130.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mondello P, Ansell SM, Nowakowski GS. Immune epigenetic crosstalk between malignant B cells and the tumor microenvironment in B cell lymphoma. Front Genet. 2022;13:826594.

  10. He MY, Tong KI, Liu T, Hawkins RW, Shelton V, Zeng Y, et al. GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma. Leukemia. 2024. in press

  11. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-Cell lymphoma. N. Engl J Med. 2017;377:2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dickinson MJ, Carlo-Stella C, Morschhauser F, Bachy E, Corradini P, Iacoboni G, et al. Glofitamab for relapsed or refractory diffuse large B-Cell Lymphoma. N Engl J Med. 2022;387:2220–31.

  13. Ennishi D, Takata K, Béguelin W, Duns G, Mottok A, Farinha P, et al. Molecular and genetic characterization of MHC deficiency identifies ezh2 as therapeutic target for enhancing immune recognition. Cancer Discov. 2019;9:546–63.

    Article  PubMed  Google Scholar 

  14. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl J Med. 2015;372:311–9.

    Article  PubMed  Google Scholar 

  15. Ansell SM, Minnema MC, Johnson P, Timmerman JM, Armand P, Shipp MA, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: A single-arm, phase II study. J Clin Oncol. 2019;37:481–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nowakowski GS, Yoon DH, Peters A, Mondello P, Joffe E, Fleury I, et al. Improved efficacy of Tafasitamab plus Lenalidomide versus systemic therapies for relapsed/refractory DLBCL: RE-MIND2, an observational retrospective matched cohort study. Clin Cancer Res. 2022;28:4003–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nowakowski GS, Yoon DH, Mondello P, Joffe E, Peters A, Fleury I, et al. RE-MIND2: comparative effectiveness of tafasitamab plus lenalidomide versus polatuzumab vedotin/bendamustine/rituximab (pola-BR), CAR-T therapies, and lenalidomide/rituximab (R2) based on real-world data in patients with relapsed/refractory diffuse large B-cell lymphoma. Ann Hematol. 2023;102:1773–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7:e511–e522.

    Article  PubMed  Google Scholar 

  19. Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22:790–800.

    Article  CAS  PubMed  Google Scholar 

  20. Wilson WH, Wright GW, Huang DW, Hodkinson B, Balasubramanian S, Fan Y, et al. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell. 2021;39:1643–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mondello P, Brea EJ, De Stanchina E, Toska E, Chang AY, Fennell M, et al. Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265 mutations. JCI Insight. 2017;2:e90196.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu Y, Mondello P, Erazo T, Tannan NB, Asgari Z, de Stanchina E, et al. NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proc Natl Acad Sci. 2018;115:12034–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mondello P, Derenzini E, Asgari Z, Philip J, Brea EJ, Seshan V, et al. Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma. Oncotarget. 2017;8:14017–28.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, et al. Polatuzumab Vedotin in previously untreated diffuse large B-Cell Lymphoma. N. Engl J Med. 2022;386:351–63.

    Article  CAS  PubMed  Google Scholar 

  25. Ysebaert L, Lemonnier F, Brisou G, Casasnovas O, Pica GM, Bachy E, et al. Tazemetostat in combination with R-CHOP in patients with high-risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II study from the Lysa. Blood. 2023;142:297.

    Article  Google Scholar 

Download references

Acknowledgements

P.M. is supported by the LRF Clinical Investigator Award (CDA 1020588), the Gerstner Family Career Development Award, the ASH RTAF, and the Junior Faculty Scholar Award.

Author information

Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Patrizia Mondello

Authors
  1. Patrizia Mondello
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PM planned, developed, and agreed to submit for publication and take responsibility for the content of this typescript.

Corresponding author

Correspondence to Patrizia Mondello.

Ethics declarations

Competing interests

The Author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mondello, P. Silencing GNAS enhances HDAC3i efficacy in CREBBP wild type B cell lymphoma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02355-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41375-024-02355-y

Search

Advanced search

Quick links