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 1,2,* , Zijun Y. Xu-Monette 2,* , Lijuan Deng 2 , Qi Shen 2 , Ganiraju C. Manyam 3 , Azahara Martinez-Lopez 4 , Li Zhang 3 , Santiago Montes-Moreno 4 , Carlo Visco 5 , Alexandar Tzankov 6 , Lihui Yin 2 , Karen Dybkaer 7 , April Chiu 8 , Attilio Orazi 9 , Youli Zu 10 , Govind Bhagat 11 , Kristy L. Richards 12 , Eric D. Hsi 13 , William W.L. Choi 14 , J. Han van Krieken 15 , Jooryung Huh 16 , Maurilio Ponzoni 17 , Andres J.M. Ferreri 17 , Xiaoying Zhao 18 , Michael B. Moller 19 , John P. Farnen 20 , Jane N. Winter 21 , Miguel A. Piris 4 , Lan Pham 2 and Ken H. Young 2,22 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 * These authors made equal contributions to this work Correspondence: Ken H. Young, email: // Keywords : CXCR4, DLBCL, BCL2, Myc, TP53 mutation Received : December 30, 2014 Accepted : January 04, 2015 Published : January 21, 2015 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.