title: Impaired class switch recombination (CSR) in Waldenstrom macroglobulinemia (WM) despite apparently normal CSR machinery.
abstract: Analysis of clonotypic isotype class switching (CSR) in Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) reveals a normal initial phase of B-cell activation as determined by constitutive and inducible expression of activation-induced cytidine deaminase (AID). Switch mu (Smu) analysis shows that large deletions are not common in WM or IgM MGUS. In CD40L/IL-4-stimulated WM cultures from 2 patients, we observed clonotypic IgG exhibiting intraclonal homogeneity associated with multiple hybrid Smu/Sgamma junctions. This suggests CSR had occurred within WM cells. Nevertheless, the estimated IgG/IgM-cell frequency was relatively low (1/1600 cells). Thus, for the majority of WM B cells, CSR does not occur even when stimulated in vitro, suggesting that the WM cell is constitutively unable to or being prevented from carrying out CSR. In contrast to WM, the majority of IgM MGUS clones exhibit intraclonal heterogeneity of IgH VDJ. Furthermore, most IgM MGUS accumulate more mutations in the upstream Smu region than do WM, making them unlikely WM progenitors. These observations suggest that switch sequence analysis may identify the subset of patients with IgM MGUS who are at risk of progression to WM.
authors.affiliation: Department of Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, AB, Canada T6G 1Z2.
authors.forename: Jitra
authors.initials: J
authors.lastname: Kriangkum
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Taylor
authors.forename: Erin
authors.initials: E
authors.lastname: Strachan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mant
authors.forename: Tony
authors.initials: T
authors.lastname: Reiman
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Belch
authors.forename: Linda M
authors.initials: LM
authors.lastname: Pilarski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics; D017931:DNA Primers; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000276:immunology*
chemical_list: D017931:DNA Primers; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D003564:Cytidine Deaminase