Journal
ONCOTARGET
Volume 6, Issue 8, Pages 5597-5614Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3343
Keywords
CXCR4; DLBCL; BCL2; Myc; TP53 mutation
Categories
Funding
- University of Texas MD Anderson Cancer Center Institutional Research Grant Award
- MD Anderson Lymphoma and Myeloma Specialized Programs of Research Excellence (SPORE) Research Development Program Awards
- MD Anderson Collaborative Research Funds with High-Throughput Molecular Diagnostics
- Gilead Pharmaceutical
- Roche Molecular Systems
- National Cancer Institute
- National Institutes of Health [R01CA138688, R01CA187415]
- Medical School of Taizhou University Scholarship Award
- MD Anderson Pathology Fellowship Award
- Harold C. and Mary L. Daily Endowment Fellowships
- Shannon Timmins Fellowship for Leukemia Research Award
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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.
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