C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma

Blood. 2014 Jun 26;123(26):4120-31. doi: 10.1182/blood-2014-03-564583. Epub 2014 Apr 7.


The C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in modulating cell trafficking in hematopoietic stem cells and clonal B cells. We screened 418 patients with B-cell lymphoproliferative disorders and described the presence of the C1013G/CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis-associated mutation in 28.2% (37/131) of patients with lymphoplasmacytic lymphoma (Waldenström macroglobulinemia [WM]), being either absent or present in only 7% of other B-cell lymphomas. In vivo functional characterization demonstrates its activating role in WM cells, as demonstrated by significant tumor proliferation and dissemination to extramedullary organs, leading to disease progression and decreased survival. The use of a monoclonal antibody anti-CXCR4 led to significant tumor reduction in a C1013G/CXCR4 WM model, whereas drug resistance was observed in mutated WM cells exposed to Bruton's tyrosine kinase, mammalian target of rapamycin, and phosphatidylinositol 3-kinase inhibitors, but not proteasome inhibitors. These findings demonstrate that C1013G/CXCR4 is an activating mutation in WM and support its role as a critical regulator of WM molecular pathogenesis and as an important therapeutic target.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Disease-Free Survival
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Mutation, Missense*
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Survival Rate
  • Waldenstrom Macroglobulinemia / drug therapy
  • Waldenstrom Macroglobulinemia / genetics
  • Waldenstrom Macroglobulinemia / metabolism*
  • Waldenstrom Macroglobulinemia / mortality
  • Waldenstrom Macroglobulinemia / pathology


  • CXCR4 protein, human
  • Enzyme Inhibitors
  • Receptors, CXCR4