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 overexpressionin de nava diffuse large B cell lymphoma (DLBCL) is unknown. n 743 patfents with de novo diffuse large B celllymphoma (DLBCL) who recelved standard Rltuxlmab-CHOPimmunochemotherapy,we assessed the expression of CXCR4 and dlSHCted its prognostic signiftcenceIn various DLBCL subsets. Our results showed that CXCR4+ patients was associated wlth mala,bulky tumor,high Ki-67indax,actlvatfld B-cell-like (ABC) subtype,and Myc,Bcl-2 or p53 overexpression.Moreover, CXCR4+ was an independent factor predictlng poorer progression-free survival n germinal­ center B-cell-like (GCB)-DLBCL,but not In ABC-DLBCL; and in patients wlth an IPI of S2,but not in those with an IPl>2. The lack of prognostic signiflcance of CXCR4 In ABC-DLBCL was likely due to the actlvatlon of p53 tumor suppressor attenuatlng CXCR4 signaling. Furthermore,concurrent CXCR4+ and BCL2 translocatlon showed dlsmal outcomes resembling but lndependent of MYC/ BCL2 double-hlt DLBCL.Gene expression profiling suggested that alteratlons in the tumor microenvlronment and lmmune responses,increased tumor prollferation and survival,and the dlsseminatlon of CXCR4+ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4+ associated poor prognosis.