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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

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

OriginalsprogEngelsk
TidsskriftOncoTarget
Vol/bind10
Nummer7
Sider (fra-til)717-731
Antal sider15
ISSN1949-2553
DOI
StatusUdgivet - 22 jan. 2019

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