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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Maria Bach Laursen
  • Linn Reinholdt, Aalborg University
  • ,
  • Anna Amanda Schönherz
  • Hanne Due, Aalborg University
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  • Ditte Starberg Jespersen, Aalborg University
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  • Lykke Grubach, Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark.
  • ,
  • Marianne Schmidt Ettrup, Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark.
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  • Rasmus Røge, Department of Hematopathology, Aalborg University Hospital, Aalborg, Denmark.
  • ,
  • Steffen Falgreen, Aalborg University
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  • Suzette Sørensen, Aalborg University, Centre for Clinical Research, Department of Obstetrics and Gynaecology, North Denmark Regional Hospital, Bispensgade 37, 9800, Hjoerring, Denmar
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  • Julie Støve Bødker, Aalborg University, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
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  • Alexander Schmitz, Aalborg University, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
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  • Hans E Johnsen, Aalborg University, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
  • ,
  • Martin Bøgsted
  • Karen Dybkær, Aalborg University, Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.

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
Issue7
Pages (from-to)717-731
Number of pages15
ISSN1949-2553
DOIs
Publication statusPublished - 22 Jan 2019
Externally publishedYes

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