title: Leukemic B cells clonally identical to myeloma plasma cells are myelomagenic in NOD/SCID mice.
abstract: OBJECTIVE
  In multiple myeloma (MM), the immunoglobulin gene rearrangement characterizing malignant plasma cells is unique. For a patient with multiple myeloma who underwent a B-cell leukemic blast transformation, using the immunoglobulin molecular signature, we characterized the clonal relationship to autologous plasma cells and the impact on normal polyclonal B-lymphocyte populations.
  
  
  METHODS
  Single-cell reverse transcriptase polymerase chain reaction (RT-PCR)/PCR was used to determine the clonal relationship between autologous MM plasma cells and leukemic B cells. A murine xenograft model was used to determine the myelomagenic potential of the leukemic B cells.
  
  
  RESULTS
  Single-cell analysis showed that circulating leukemic-phase cells were clonotypic, with an IgH VDJ sequence identical to that of diagnosis plasma cells. Analysis of IgH transcripts indicates MM clonal dominance over normal B-cell components of the immune system at diagnosis and during leukemic disease. Leukemic B cells were xenografted to irradiated NOD/SCID mice, leading to lytic bone lesions and clonotypic cells in murine BM. Although human cells in murine BM expressed CD138, a marker largely absent from ex vivo leukemic cells, the expression of CD45, CD19, and CD20 confirmed that engrafting cells were mature, probably late-stage B cells rather than plasma cells.
  
  
  CONCLUSIONS
  Leukemic B cells are able to exert strong clonal dominance over normal components of the immune system, colonize the murine BM in a xenograft model, and disrupt normal bone metabolism leading to lytic bone lesions. This supports the hypothesis that clonotypic MM B cells are reservoirs of disease that persist throughout therapy and give rise to relapse.
authors.affiliation: Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada. lpilarski@gpu.srv.ualberta.ca
authors.forename: Linda M
authors.initials: LM
authors.lastname: Pilarski
authors.forename: Karen
authors.initials: K
authors.lastname: Seeberger
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coupland
authors.forename: Alana
authors.initials: A
authors.lastname: Eshpeter
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Keats
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Taylor
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Belch
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis; D018951:Antigens, CD20 / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001853:Bone Marrow / Q000473:pathology*; D002999:Clone Cells / Q000473:pathology*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009368:Neoplasm Transplantation; D010950:Plasma Cells / Q000473:pathology; D011509:Proteoglycans / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053668:Syndecan-1; D053667:Syndecans; D014183:Transplantation, Heterologous
chemical_list: D018941:Antigens, CD19; D018951:Antigens, CD20; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D012333:RNA, Messenger; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D017493:Leukocyte Common Antigens