Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma

Jiayu Chen, Zijun Y. Xu-Monette, Lijuan Deng, Qi Shen, Ganiraju C. Manyam, Azahara Martinez-Lopez, Li Zhang, Santiago Montes-Moreno, Carlo Visco, Alexandar Tzankov, Lihui Yin, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W L Choi, J. Han van KriekenJooryung Huh, Maurilio Ponzoni, Andrés J M Ferreri, Xiaoying Zhao, Michael B. Møller, John P. Farnen, Jane N. Winter, Miguel A. Piris, Lan Pham, Ken H. Young

Research output: Contribution to journalArticle

Abstract

Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4+ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4+ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of ≤2, but not in those with an IPI > 2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4+ and BCL2 translocation showed dismal outcomes resembling but independent of MYC/BCL2 double-hit DLBCL. Gene expression profiling suggested that alterations in the tumor microenvironment and immune responses, increased tumor proliferation and survival, and the dissemination of CXCR4+ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4+ associated poor prognosis.

Original languageEnglish
Pages (from-to)5597-5614
Number of pages18
JournalOncotarget
Volume6
Issue number8
Publication statusPublished - 2015

Keywords

  • BCL2
  • CXCR4
  • DLBCL
  • Myc
  • TP53 mutation

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Chen, J., Xu-Monette, Z. Y., Deng, L., Shen, Q., Manyam, G. C., Martinez-Lopez, A., Zhang, L., Montes-Moreno, S., Visco, C., Tzankov, A., Yin, L., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W. L., ... Young, K. H. (2015). Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma. Oncotarget, 6(8), 5597-5614.