CD19-CD45 low/- CD38 high/CD138+ plasma cells enrich for human tumorigenic myeloma cells.
Multiple myeloma is a hematological neoplasm characterized by the accumulation of clonal plasma cells in the bone marrow. Its frequent relapse following achievement of clinical remissions implicates the existence of therapy-resistant myeloma-initiating cells. To date, results on the identity of myeloma-initiating cells have differed. Here, we prospectively identified a myeloma-initiating population by fractionating and transplanting patient bone marrow cells into human bone-bearing immunocompromised mice. Xenotransplantation of fractionated CD138(+)/CD38(high) cells from 40% of patients (8/20) led to a repopulation of CD19(+)CD38(low) or CD138(+)CD38(+) B-lineage cells in human bone grafts; and these grafts were clonally derived from patient myeloma cells. Meanwhile, CD19(+)CD38(low) xenografts were detected in human bone-bearing mice transplanted with CD19(+)CD38(low/-) B cells from 8 of 22 samples but were not clonally related to patient myeloma cells. Further fractionation and xenotransplantation of CD138(+)CD38(high) cells demonstrated that (CD45(low/-) or CD19(-)) CD38(high)/CD138(+) plasma cells, but not (CD45(high) or CD19(+)) CD38(high)/CD138(+) plasmablasts enrich for myeloma-initiating cells. Quantitative reverse transcription-PCR of two serially transplantable xenografts, which were CD19(-)CD138(+), revealed that they were Pax5 (a B-cell-specific transactivator)-negative. These results suggest that CD19(-)CD45(low/-) fully differentiated plasma cells enrich for long-lived and tumor-initiating cells whereas B cells or plasmablasts do not.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. kimdk1@stanford.edu
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Kim
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Park
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Medeiros
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Weissman
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis*; D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D005333:Fetus / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000032:analysis*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology*; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053668:Syndecan-1 / Q000032:analysis*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018941:Antigens, CD19; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; C508241:SDC1 protein, human; D053668:Syndecan-1; D017493:Leukocyte Common Antigens; D051997:ADP-ribosyl Cyclase 1