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.

  • Letter
  • Published:

Lymphoma

Targeting BCL-W and BCL-XL as a therapeutic strategy for Hodgkin lymphoma

Leukemia volume 34, pages 947–952 (2020)Cite this article

Subjects

Hodgkin lymphoma (HL), accounting for ~10% of lymphomas diagnosed in the United States [1], have a largely favorable outcome (5-year survival 85%) that may be improved with anti-CD30-drug conjugates or checkpoint inhibitors [2, 3]. However, relapsed/refractory HL has poor outcomes and necessitates intensive salvage chemotherapy and/or autologous hematopoietic cell transplantation [4]. Factors classifying HL relapse/refractory risk are needed for determining optimal treatment strategies [5]. Therefore, identifying key factors underlying the mechanisms of HL cell survival and maintenance are necessary to uncover new therapeutic targets and/or develop innovative strategies to increase cure rates and long-term disease control while limiting toxicities in HL patients.

Apoptotic signals triggered by oncogenic stress or chemotherapies are countered by increased expression of anti-apoptotic BCL-2 family members [6]. Consequently, specific inhibitors to anti-apoptotic family members (BCL-2, BCL-XL, MCL-1) have been developed, such as venetoclax that inhibits BCL-2 [7]. Unfortunately, most B-cell lymphomas have proven resistant to venetoclax, likely due to their dependency on other anti-apoptotic BCL-2 family proteins [8]. Our analysis of ∼2300 B-cell lymphoma samples revealed the understudied anti-apoptotic BCL-2 family member BCL-W was elevated in six different types of B-cell lymphoma, including HL [9]. We report here a comprehensive investigation into the contribution of BCL-W in HL cell survival, a mechanism of its overexpression, and its potential as a diagnostic and prognostic biomarker for HL.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1
Fig. 2

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  2. Connors JM, Radford JA. Brentuximab vedotin for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:1560–1.

    Article  Google Scholar 

  3. Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II checkMate 205 trial. J Clin Oncol. 2018;36:1428–39.

    Article  CAS  Google Scholar 

  4. Shanbhag S, Ambinder RF. Hodgkin lymphoma: a review and update on recent progress. CA Cancer J Clin. 2018;68:116–32.

    Article  Google Scholar 

  5. Ansell SM. Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc. 2015;90:1574–83.

    Article  Google Scholar 

  6. Montero J, Letai A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 2018;25:56–64.

    Article  CAS  Google Scholar 

  7. Adams CM, Clark-Garvey S, Porcu P, Eischen CM. Targeting the Bcl-2 family in B cell lymphoma. Front Oncol. 2018;8:636.

    Article  Google Scholar 

  8. Davids MS. Targeting BCL-2 in B-cell lymphomas. Blood. 2017;130:1081–8.

    Article  CAS  Google Scholar 

  9. Adams CM, Mitra R, Gong JZ, Eischen CM. Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW. Clin Cancer Res. 2017;23:7119–29.

    Article  CAS  Google Scholar 

  10. Schlaifer D, March M, Krajewski S, Laurent G, Pris J, Delsol G, et al. High expression of the bcl-x gene in Reed–Sternberg cells of Hodgkin’s disease. Blood. 1995;85:2671–4.

    Article  CAS  Google Scholar 

  11. Xerri L, Parc P, Brousset P, Schlaifer D, Hassoun J, Reed JC, et al. Predominant expression of the long isoform of Bcl-x (Bcl-xL) in human lymphomas. Br J Haematol. 1996;92:900–6.

    Article  CAS  Google Scholar 

  12. Herling M, Rassidakis GZ, Medeiros LJ, Vassilakopoulos TP, Kliche KO, Nadali G, et al. Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed–Sternberg cells of classical Hodgkin’s lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome. Clin Cancer Res. 2003;9:2114–20.

    CAS  PubMed  Google Scholar 

  13. Kawasaki T, Yokoi S, Tsuda H, Izumi H, Kozaki K, Aida S, et al. BCL2L2 is a probable target for novel 14q11.2 amplification detected in a non-small cell lung cancer cell line. Cancer Sci. 2007;98:1070–7.

    Article  CAS  Google Scholar 

  14. Ju W, Zhang M, Wilson KM, Petrus MN, Bamford RN, Zhang X, et al. Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin’s lymphoma. Proc Natl Acad Sci USA. 2016;113:1624–9.

    Article  CAS  Google Scholar 

  15. Jayanthan A, Howard SC, Trippett T, Horton T, Whitlock JA, Daisley L, et al. Targeting the Bcl-2 family of proteins in Hodgkin lymphoma: in vitro cytotoxicity, target modulation and drug combination studies of the Bcl-2 homology 3 mimetic ABT-737. Leuk Lymphoma. 2009;50:1174–82.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Zhijiu Zhong for performing the IHC in the Translational Research and Pathology Shared Resource Core and members of the Eischen lab for helpful discussion.

Funding

The Flow Cytometry and Translational Research and Pathology Shared Resource Cores was supported by the NCI Cancer Center grant P30CA056036. Support for this study was also provided by NCI grant CA236853, the Pellini Foundation Fund, the Herbert A. Rosenthal, MD ‘56 Endowed Chair fund, and the Sidney Kimmel Cancer Center.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Clare M. Adams, Ramkrishna Mitra & Christine M. Eischen

  2. Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

    Ashley N. Vogel, Jinglan Liu & Jerald Z. Gong

Authors
  1. Clare M. Adams
    View author publications

    Search author on:PubMed Google Scholar

  2. Ramkrishna Mitra
    View author publications

    Search author on:PubMed Google Scholar

  3. Ashley N. Vogel
    View author publications

    Search author on:PubMed Google Scholar

  4. Jinglan Liu
    View author publications

    Search author on:PubMed Google Scholar

  5. Jerald Z. Gong
    View author publications

    Search author on:PubMed Google Scholar

  6. Christine M. Eischen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

CMA and CME designed the experiments; RM performed the bioinformatic analyses; JZG identified the patient samples; JZG, JL, and ANV performed the FISH and IHC analysis; CMA, RM, JZG, and CME analyzed and interpreted the data; CMA, RM, and CME wrote the manuscript; all authors edited and approved the manuscript.

Corresponding author

Correspondence to Christine M. Eischen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adams, C.M., Mitra, R., Vogel, A.N. et al. Targeting BCL-W and BCL-XL as a therapeutic strategy for Hodgkin lymphoma. Leukemia 34, 947–952 (2020). https://doi.org/10.1038/s41375-019-0611-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41375-019-0611-9

This article is cited by

Search

Advanced search

Quick links