Analysis of clonotypic switch junctions reveals multiple myeloma originates from a single class switch event with ongoing mutation in the isotype-switched progeny.
Multiple myeloma (MM) is a cancer of plasma cells (PCs) expressing immunoglobulin heavy chain (IgH) postswitch isotypes. The discovery of earlier stage cells related to postswitch PCs, called preswitch clonotypic IgM (cIgM) cells led to the hypothesis that cIgM cells may be MM progenitors, replenishing the tumor throughout malignancy. cIgM cells may do this by undergoing class switch recombination (CSR), a process detectable in postswitch PCs as multiple IgH switch junctions associated with a single clonotypic IgH V/D/J. We addressed this with a specific clonotypic-switch polymerase chain reaction (PCR), informative for 32 of 41 cases. Here we made 2 significant discoveries: (1) in all cases, we detected only a single clonotypic switch fragment that persists over time (1-7.6 years), and (2) we detected ongoing mutation upstream of the switch junction in 5 of 6 patients, often targeting the intronic enhancer, a key control region in IgH expression. The presence of a single, unchanging clonotypic switch junction suggests that cIgM cells are not MM-PC progenitors; rather, postswitch PCs arise from a single cIgM cell, and MM-PC progenitors reside in the postswitch population. Furthermore, mutations revealed here provide a new marker to identify MM-PC progenitors and aggressive clones that evolve throughout malignancy.
Taylor
Brian J
BJ
Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Canada.
Kriangkum
Jitra
J
Pittman
Julie A
JA
Mant
Michael J
MJ
Reiman
Tony
T
Belch
Andrew R
AR
Pilarski
Linda M
LM
D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D017578:Immunoglobulin Class Switching; D007134:Immunoglobulin Switch Region; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology; D016133:Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D027041:Somatic Hypermutation, Immunoglobulin; D013997:Time Factors
D017931:DNA Primers; D004273:DNA, Neoplasm