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Oncotarget. 2015 Mar 20;6(8):5597-614.

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

Author information

1
Medical School of Taizhou University, Taizhou, Zhejiang, China.
2
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Hospital Universitario Marques de Valdecilla, Santander, Spain.
5
San Bortolo Hospital, Vicenza, Italy.
6
University Hospital, Basel, Switzerland.
7
Aalborg University Hospital, Aalborg, Denmark.
8
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
9
Weill Medical College of Cornell University, New York, NY, USA.
10
The Methodist Hospital, Houston, TX, USA.
11
Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
12
University of North Carolina School of Medicine, Chapel Hill, NC, USA.
13
Cleveland Clinic, Cleveland, OH, USA.
14
University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.
15
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
16
Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea.
17
San Raffaele H. Scientific Institute, Milan, Italy.
18
Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China.
19
Odense University Hospital, Odense, Denmark.
20
Gundersen Lutheran Health System, La Crosse, WI, USA.
21
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
22
The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX, USA.

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:

BCL2; CXCR4; DLBCL; Myc; TP53 mutation

PMID:
25704881
PMCID:
PMC4467389
DOI:
10.18632/oncotarget.3343
[Indexed for MEDLINE]
Free PMC Article

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