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

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.

• Authors: 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 Krieken, Jooryung 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 8 Pg. 5597-614 (Mar 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25704881 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• BKT140
• CXCL12 protein, human
• CXCR4 protein, human
• Chemokine CXCL12
• Oligopeptides
• R-CHOP protocol
• Receptors, CXCR4
• TP53 protein, human
• Tumor Suppressor Protein p53
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• Prednisone

Topics

• Antibodies, Monoclonal, Murine-Derived (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Cell Survival (physiology)
• Chemokine CXCL12 (biosynthesis, genetics)
• Cyclophosphamide (administration & dosage)
• Disease Progression
• Doxorubicin (administration & dosage)
• Female
• Gene Expression Regulation, Neoplastic
• Germinal Center (pathology)
• Humans
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, metabolism, pathology)
• Male
• Middle Aged
• Mutation
• Oligopeptides (pharmacology)
• Prednisone (administration & dosage)
• Prognosis
• Receptors, CXCR4 (antagonists & inhibitors, biosynthesis, genetics)
• Rituximab (administration & dosage)
• Transcriptome
• Tumor Suppressor Protein p53 (genetics)
• Vincristine (administration & dosage)