title: Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance.
abstract: Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138(+) multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138(neg) B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138(+) multiple myeloma plasma cells but had little effect on CD138(neg) precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138(neg) cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. matsuwi@jhmi.edu
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
authors.forename: James P
authors.initials: JP
authors.lastname: Barber
authors.forename: Sarah
authors.initials: S
authors.lastname: Brennan
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.forename: Ian
authors.initials: I
authors.lastname: McNiece
authors.forename: Lan
authors.initials: L
authors.lastname: Lin
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.forename: Craig
authors.initials: C
authors.lastname: Peacock
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Huff
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077269:Lenalidomide; D051379:Mice; D008815:Mice, Inbred Strains; D009101:Multiple Myeloma / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010950:Plasma Cells / Q000187:drug effects* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology; D053668:Syndecan-1 / Q000032:analysis; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D014410:Tumor Stem Cell Assay
chemical_list: D018951:Antigens, CD20; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053668:Syndecan-1; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C012358:4-hydroxycyclophosphamide; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide; D000077269:Lenalidomide