Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma Journal Article
| Authors: | 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.; Han van Krieken, J.; Huh, J.; Ponzoni, M.; Ferreri, A. J.; Zhao, X.; Møller, M. B.; Farnen, J. P.; Winter, J. N.; Piris, M. A.; Pham, L.; Young, K. H. |
| Article Title: | 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. |
| Keywords: | signal transduction; adult; controlled study; human tissue; protein expression; unclassified drug; gene mutation; major clinical study; prednisone; doxorubicin; rituximab; ki 67 antigen; cell survival; protein bcl 2; metastasis; progression free survival; gene expression profiling; tumor volume; cyclophosphamide; vincristine; in vitro study; protein p53; prediction; cancer inhibition; tumor suppressor gene; immune response; bcl2; myc protein; lymphoma cell; large cell lymphoma; tumor growth; cancer classification; gender; myc; dlbcl; chemokine receptor cxcr4; tp53 mutation; cxcr4; cancer prognosis; chemokine receptor cxcr4 antagonist; human; male; female; article; btk 140; activated b cell like diffuse large b cell lymphoma; germinal center b cell like diffuse large b cell lymphoma |
| Journal Title: | Oncotarget |
| Volume: | 6 |
| Issue: | 8 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2015-03-20 |
| Start Page: | 5597 |
| End Page: | 5614 |
| Language: | English |
| PROVIDER: | scopus |
| PUBMED: | 25704881 |
| PMCID: | PMC4467389 |
| DOI: | 10.18632/oncotarget.3343 |
| DOI/URL: | |
| Notes: | Export Date: 4 May 2015 -- Source: Scopus |
