High CXCR4 expression impairs rituximab response and the prognosis of R-CHOP-treated diffuse large B-cell lymphoma patients
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Maria Bach Laursen1,*, Linn Reinholdt1,*, Anna Amanda Schönherz1, Hanne Due1, Ditte Starberg Jespersen1, Lykke Grubach5, Marianne Schmidt Ettrup5, Rasmus Røge5, Steffen Falgreen1, Suzette Sørensen1,2,4, Julie Støve Bødker1,3, Alexander Schmitz1,3, Hans E. Johnsen1,3,4, Martin Bøgsted1,3,4 and Karen Dybkær1,3,4
1Department of Hematology, Aalborg University Hospital, Aalborg, Denmark
2Centre for Clinical Research, North Denmark Regional Hospital, Hjørring, Denmark
3Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
4Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
5Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark
*These authors have contributed equally to this work
Karen Dybkær, email: [email protected]
Keywords: CXCR4; rituximab; diffuse large B-cell lymphoma (DLBCL); prognosis; drug sensitivity
Received: November 19, 2018 Accepted: December 29, 2018 Published: January 22, 2019
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.
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