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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

Shimin Hu, Zijun Y. Xu-Monette, Alexander Tzankov, Tina Green, Lin Wu, Aarthi Balasubramanyam, Wei-min Liu, Carlo Visco, Yong Li, Roberto N. Miranda, Santiago Montes-Moreno, Karen Dybkær, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, Xiaoying Zhao, J. Han van Krieken, Qin Huang, Jooryung Huh, Weiyun Ai, Maurilio Ponzoni, Andrés J.M. Ferreri, Fan Zhou, Graham W. Slack, Randy D. Gascoyne, Meifeng Tu, Daina Variakojis, Weina Chen, Ronald S. Go, Miguel A. Piris, Michael B. Møller, L. Jeffrey Medeiros, Ken H. Young

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.