Blood Journal
Leading the way in experimental and clinical research in hematology

MYC/BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study

  1. Shimin Hu1,
  2. Zijun Y. Xu-Monette1,
  3. Alexander Tzankov2,
  4. Tina Green3,
  5. Lin Wu4,
  6. Aarthi Balasubramanyam4,
  7. Wei-min Liu4,
  8. Carlo Visco5,
  9. Yong Li6,
  10. Roberto N. Miranda1,
  11. Santiago Montes-Moreno7,
  12. Karen Dybkær8,
  13. April Chiu9,
  14. Attilio Orazi10,
  15. Youli Zu11,
  16. Govind Bhagat12,
  17. Kristy L. Richards13,
  18. Eric D. Hsi14,
  19. William W.L. Choi15,
  20. Xiaoying Zhao16,
  21. J. Han van Krieken17,
  22. Qin Huang18,
  23. Jooryung Huh19,
  24. Weiyun Ai20,
  25. Maurilio Ponzoni21,
  26. Andrés J.M. Ferreri22,
  27. Fan Zhou22,
  28. Graham W. Slack23,
  29. Randy D. Gascoyne23,
  30. Meifeng Tu24,
  31. Daina Variakojis25,
  32. Weina Chen26,
  33. Ronald S. Go27,
  34. Miguel A. Piris7,
  35. Michael B. Møller3,
  36. L. Jeffrey Medeiros1, and
  37. Ken H. Young1,*
  1. 1 Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States;
  2. 2 University Hospital, Basel, Switzerland;
  3. 3 Odense University Hospital, Odense, Denmark;
  4. 4 Roche Molecular Systems, Pleasanton, CA, United States;
  5. 5 San Bortolo Hospital, Vicenza, Italy;
  6. 6 University of Louisville, Louisville, KY, United States;
  7. 7 Hospital Universitario Marques de Valdecilla, Santander, Spain;
  8. 8 Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark;
  9. 9 Memorial Sloan-Kettering Cancer Center, New York, NY, United States;
  10. 10 Weill Medical College of Cornell University, New York, NY, United States;
  11. 11 The Methodist Hospital, Houston, TX, United States;
  12. 12 Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, United States;
  13. 13 University of North Carolina School of Medicine, Chapel Hill, NC, United States;
  14. 14 Cleveland Clinic, Cleveland, OH, United States;
  15. 15 University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China;
  16. 16 Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China;
  17. 17 Radboud University Nijmegen Medical Center, Nijmegen, Netherlands;
  18. 18 City of Hope National Medical Center, Duarte, CA, United States;
  19. 19 Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea, Republic of;
  20. 20 University of California San Francisco School of Medicine, San Francisco, CA, United States;
  21. 21 San Raffaele H. Scientific Institute, Milan, Italy;
  22. 22 Southwest Washington Medical Center, Vancouver, WA, United States;
  23. 23 BC Cancer Agency and BC Cancer Research Centre, Vancouver, BC, Canada;
  24. 24 Peking University School of Oncology, Beijing Cancer Hospital, Beijing, China;
  25. 25 Feinberg School of Medicine, Northwestern University, Chicago, IL, United States;
  26. 26 Ameripath Diagnostics, Dallas, TX, United States;
  27. 27 Gundersen Lutheran Health System, La Crosse, WI, United States
  1. * Corresponding author; email: khyoung{at}mdanderson.org

Key points

  • DLBCL patients with MYC/BCL2 co-expression show inferior outcome with high-risk gene expression signature

Abstract

Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes according to their gene-expression signatures. In this study, we assessed a cohort of 893 de novo DLBCL patients treated with R-CHOP therapy. We show that MYC/BCL2 protein co-expression occurred significantly more commonly in the ABC subtype. The ABC and GCB subtypes had similar prognoses in DLBCL with MYC/BCL2 co-expression as well as in DLBCL without MYC/BCL2 co-expression. Consistent with the notion that the prognostic difference between the two subtypes was attributable to MYC/BCL2 co-expression, the difference in gene-expression signatures between the two subtypes was dramatically diminished in the absence of MYC/BCL2 co-expression. Furthermore, DLBCL with MYC/BCL2 co-expression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 co-expression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. Furthermore, the data suggest that MYC/BCL2 co-expression, rather than cell of origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP therapy.

  • Submitted October 16, 2012.
  • Accepted February 19, 2013.