TY - JOUR
T1 - Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma
AU - Chen, Jiayu
AU - Xu-Monette, Zijun Y.
AU - Deng, Lijuan
AU - Shen, Qi
AU - Manyam, Ganiraju C.
AU - Martinez-Lopez, Azahara
AU - Zhang, Li
AU - Montes-Moreno, Santiago
AU - Visco, Carlo
AU - Tzankov, Alexandar
AU - Yin, Lihui
AU - Dybkaer, Karen
AU - Chiu, April
AU - Orazi, Attilio
AU - Zu, Youli
AU - Bhagat, Govind
AU - Richards, Kristy L.
AU - Hsi, Eric D.
AU - Choi, William W.L.
AU - Han van Krieken, J.
AU - Huh, Jooryung
AU - Ponzoni, Maurilio
AU - Ferreri, Andrés J.M.
AU - Zhao, Xiaoying
AU - Møller, Michael B.
AU - Farnen, John P.
AU - Winter, Jane N.
AU - Piris, Miguel A.
AU - Pham, Lan
AU - Young, Ken H.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - BCL2
KW - CXCR4
KW - DLBCL
KW - Myc
KW - TP53 mutation
UR - http://www.scopus.com/inward/record.url?scp=84925633757&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925633757&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3343
DO - 10.18632/oncotarget.3343
M3 - Article
C2 - 25704881
AN - SCOPUS:84925633757
VL - 6
SP - 5597
EP - 5614
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 8
ER -