High CXCR4 expression impairs rituximab response and the prognosis of R-CHOP-treated diffuse large B-cell lymphoma patients.

Autor:	Laursen MB; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark., Reinholdt L; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark., Schönherz AA; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark., Due H; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark., Jespersen DS; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark., Grubach L; Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark., Ettrup MS; Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark., Røge R; Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark., Falgreen S; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark., Sørensen S; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.; Centre for Clinical Research, North Denmark Regional Hospital, Hjørring, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Bødker JS; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark., Schmitz A; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark., Johnsen HE; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Bøgsted M; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Dybkær K; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Jan 22; Vol. 10 (7), pp. 717-731. Date of Electronic Publication: 2019 Jan 22 (Print Publication: 2019).
DOI:	10.18632/oncotarget.26588
Abstrakt:	Survival of diffuse large B-cell lymphoma (DLBCL) patients has improved by inclusion of rituximab. Refractory/recurrent disease caused by treatment resistance is, however, a major problem. Determinants of rituximab sensitivity are not fully understood, but effect of rituximab are enhanced by antagonizing cell surface receptor CXCR4. In a two-step strategy, we tested the hypothesis that prognostic value of CXCR4 in DLBCL relates to rituximab treatment, due to a hampering effect of CXCR4 on the response of DLBCL cells to rituximab. First, by investigating the prognostic impact of CXCR4 mRNA expression separately for CHOP (n=181) and R-CHOP (n=233) cohorts and, second, by assessing the interaction between CXCR4 and rituximab in DLBCL cell lines. High CXCR4 expression level was significantly associated with poor outcome only for R-CHOP-treated patients, independent of IPI score, CD20 expression, ABC/GCB and B-cell-associated gene signature (BAGS) classifications. s. For responsive cell lines, inverse correlation was observed between rituximab sensitivity and CXCR4 surface expression, rituximab induced upregulation of surface-expressed CXCR4, and growth-inhibitory effect of rituximab increased by plerixafor, supporting negative impact of CXCR4 on rituximab function. In conclusion, CXCR4 is a promising independent prognostic marker for R-CHOP-treated DLBCL patients, possibly due to inverse correlation between CXCR4 expression and rituximab sensitivity. Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.
Databáze:	MEDLINE
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