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Br J Haematol. 2016 Mar;172(5):735-44. doi: 10.1111/bjh.13897. Epub 2015 Dec 13.

Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia.

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Bing Center for Waldenström's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Lipper Center for Multiple Myeloma, Dana Farber Cancer Institute, Boston, MA, USA.
Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Stanford University Medical Center, Stanford, CA, USA.
Department of Medical Oncology, Memorial Sloane Kettering Cancer Center, New York, NY, USA.
Haematology Unit, Niguarda Hospital, Milan, Italy.
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Department of Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.


CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.


CXCR4; IgM MGUS; MYD88 L265P; Marginal Zone Lymphoma; WHIM; Waldenström macroglobulinaemia

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