Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia Journal Article

   


Authors: Xu, L.; Hunter, Z. R.; Tsakmaklis, N.; Cao, Y.; Yang, G.; Chen, J.; Liu, X.; Kanan, S.; Castillo, J. J.; Tai, Y. T.; Zehnder, J. L.; Brown, J. R.; Carrasco, R. D.; Advani, R.; Sabile, J. M.; Argyropoulos, K.; Palomba, M. L.; Morra, E.; Trojani, A.; Greco, A.; Tedeschi, A.; Varettoni, M.; Arcaini, L.; Munshi, N. M.; Anderson, K. C.; Treon, S. P.
Article Title: Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia
Abstract: CXCR4(WHIM) somatic mutations are distinctive to Waldenstrom 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 351%, range 12-975%). 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.
Keywords: marginal zone lymphoma; resistance; features; monoclonal; cxcr4; gammopathy; ibrutinib; l265p somatic mutation; myd88 l265p; waldenström macroglobulinaemia; igm mgus; whim
Journal Title: British Journal of Haematology
Volume: 172
Issue: 5
ISSN: 0007-1048
Publisher: John Wiley & Sons  
Date Published: 2016-03-01
Start Page: 735
End Page: 744
Language: English
ACCESSION: WOS:000370959600008
DOI: 10.1111/bjh.13897
PROVIDER: wos
PUBMED: 26659815
PMCID: PMC5409813
Notes: Article -- Source: Wos
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MSK Authors
  1. Maria Lia Palomba
    415 Palomba
  2. Kimon Argyropoulos
    44 Argyropoulos
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