C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Aldo M
AM
Roccaro
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Antonio
A
Sacco
University of Salamanca, Salamanca, Spain;
Cristina
C
Jimenez
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Patricia
P
Maiso
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Michele
M
Moschetta
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Yuji
Y
Mishima
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Yosra
Y
Aljawai
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Ilyas
I
Sahin
Bristol-Myers Squibb, Redwood City, CA;
Michelle
M
Kuhne
Bristol-Myers Squibb, Redwood City, CA;
Pina
P
Cardarelli
Bristol-Myers Squibb, Lawrenceville, NJ; and.
Lewis
L
Cohen
University of Navarra, Pamplona, Spain.
Jesus F
JF
San Miguel
University of Salamanca, Salamanca, Spain;
Ramon
R
Garcia-Sanz
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
Irene M
IM
Ghobrial
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
C527276:CXCR4 protein, human; D004791:Enzyme Inhibitors; D019718:Receptors, CXCR4