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

Maria Bach Laursen, Linn Reinholdt, Anna Amanda Schönherz, Hanne Due, Ditte Starberg Jespersen, Lykke Grubach, Marianne Schmidt Ettrup, Rasmus Røge, Steffen Falgreen, Suzette Sørensen, Julie Støve Bødker, Alexander Schmitz, Hans E. Johnsen, Martin Bøgsted, Karen Dybkær*

*Corresponding author

Research output: Contribution to journalJournal articleResearchpeer-review

7 Citations (Scopus)
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Abstract

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.

Original languageEnglish
JournalOncotarget
Volume10
Issue number7
Pages (from-to)717-731
Number of pages15
ISSN1949-2553
DOIs
Publication statusPublished - 22 Jan 2019

Keywords

  • CXCR4
  • Diffuse large B-cell lymphoma (DLBCL)
  • Drug sensitivity
  • Prognosis
  • Rituximab

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