title: Molecular characterization of heavy chain immunoglobulin gene rearrangements in Waldenström's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.
abstract: OBJECTIVE
  Waldenström macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) are IgM-related disorders in which monoclonal B cells harbor a unique clonotypic rearrangement of the immunoglobulin heavy chain gene (IgH). The aim of this study was to characterize IgH rearrangements in a larger series of IgM-related disorders than any previously described.
  
  
  METHODS
  Seventy-two patients with monoclonal IgM disorders (64 with WM and eight with IgM-MGUS) were studied to amplify and sequence both VDJH and DJH rearrangements. Twenty-nine of them were also tested for the existence of class switch recombination (CSR).
  
  
  RESULTS
  VDJH and DJH rearrangements were detected in 91% and 42% of WM patients and in 100% and 13% of IgM-MGUS patients, respectively. In WM, the most frequently observed VH family and single segment were VH3 and VH3-23 (76% and 29%, respectively), with their frequencies differing markedly from those that would occur if the rearrangements were random. The VH3-23 segment was never selected in IgM-MGUS. The distribution of both DH and JH families in WM did not differ from that in normal B-lymphocytes. Somatic hypermutation with >2% deviation was seen in 90% of cases of WM and in 71% of IgM-MGUS. DJH rearrangements were more frequent in WM than in MGUS (42% and 13%, respectively). All DJH rearrangements were unmutated, which makes them an attractive target for minimal residual disease investigation. IgM clonotypic transcripts were observed in all cases and IgD in 83%. IgA and/or IgG monoclonal isotypes were seen in three WM cases (14%) but in none of the IgM-MGUS patients.
  
  
  CONCLUSIONS
  WM and IgM-MGUS exhibit dissimilarities in VDJH and DJH rearrangements that could suggest different differentiation processes. There is evidence that WM cells are able to undergo CSR in vivo, a fact that was initially thought to be impossible in this disease.
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martín-Jiménez
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Sanz
authors.forename: Ana
authors.initials: A
authors.lastname: Balanzategui
authors.forename: Miguel
authors.initials: M
authors.lastname: Alcoceba
authors.forename: Enrique
authors.initials: E
authors.lastname: Ocio
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Sanchez
authors.forename: Marcos
authors.initials: M
authors.lastname: González
authors.forename: Jesus
authors.initials: J
authors.lastname: San Miguel
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002999:Clone Cells / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D017578:Immunoglobulin Class Switching; D007075:Immunoglobulin M / Q000235:genetics*; D010265:Paraproteinemias / Q000235:genetics*; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin; D050441:VDJ Exons; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics*
chemical_list: D022801:Complementarity Determining Regions; D007075:Immunoglobulin M