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

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
Eksternt udgivetJa

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