title: Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors.
abstract: Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of β-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, Tokushima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ikegame
authors.forename: S
authors.initials: S
authors.lastname: Ozaki
authors.forename: D
authors.initials: D
authors.lastname: Tsuji
authors.forename: T
authors.initials: T
authors.lastname: Harada
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Miki
authors.forename: A
authors.initials: A
authors.lastname: Nakano
authors.forename: K
authors.initials: K
authors.lastname: Kagawa
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: M
authors.initials: M
authors.lastname: Abe
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Hiasa
authors.forename: N
authors.initials: N
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: A
authors.initials: A
authors.lastname: Sakamoto
authors.forename: K
authors.initials: K
authors.lastname: Habu
authors.forename: M
authors.initials: M
authors.lastname: Endo
authors.forename: K
authors.initials: K
authors.lastname: Itoh
authors.forename: H
authors.initials: H
authors.lastname: Yamada-Okabe
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D057127:Single-Chain Antibodies / Q000276:immunology / Q000627:therapeutic use*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D006680:HLA Antigens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D057127:Single-Chain Antibodies; D051176:beta Catenin