MYD88 L265P in Waldenström Macroglobulinemia, Immunoglobulin M Monoclonal Gammopathy, and Other B-cell Lymphoproliferative Disorders Using Conventional and Quantitative Allele-Specific Polymerase Chain Reaction

Blood. 2013 Mar 14;121(11):2051-8. doi: 10.1182/blood-2012-09-454355. Epub 2013 Jan 15.


By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Amino Acid Substitution / physiology
  • B-Lymphocytes* / metabolism
  • B-Lymphocytes* / pathology
  • Base Sequence
  • Case-Control Studies
  • Cell Transformation, Neoplastic / genetics
  • DNA Mutational Analysis
  • Humans
  • Immunoglobulin M* / genetics
  • Immunoglobulin M* / metabolism
  • Leucine / genetics
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / immunology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Monoclonal Gammopathy of Undetermined Significance / genetics*
  • Monoclonal Gammopathy of Undetermined Significance / immunology
  • Monoclonal Gammopathy of Undetermined Significance / metabolism
  • Myeloid Differentiation Factor 88 / genetics*
  • Polymerase Chain Reaction / methods*
  • Polymorphism, Single Nucleotide / physiology
  • Proline / genetics
  • Waldenstrom Macroglobulinemia / genetics*


  • Immunoglobulin M
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Proline
  • Leucine