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Myeloma

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

Leukemia volume 26, pages 2124–2134 (2012)Cite this article

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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.

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Acknowledgements

We thank Ms A Oda and H Amou for their excellent technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research (C) for SO and Scientific Research (A) for TM from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, Tokushima, Japan

    A Ikegame, S Ozaki, T Harada, S Fujii, S Nakamura, H Miki, A Nakano, K Kagawa, K Takeuchi, M Abe, K Watanabe, M Hiasa & T Matsumoto

  2. Department of Internal Medicine, Tokushima Prefectural Central Hospital, Tokushima, Japan

    S Ozaki

  3. Department of Medicinal Biotechnology, University of Tokushima Graduate School of Pharmaceutical Sciences, Tokushima, Japan

    D Tsuji & K Itoh

  4. Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan

    K Takeuchi & T Matsumoto

  5. Department of Orthodontics and Dentofacial Orthopedics, University of Tokushima Graduate School of Oral Sciences, Tokushima, Japan

    K Watanabe

  6. Department of Biomaterials and Bioengineerings, University of Tokushima Graduate School of Oral Sciences, Tokushima, Japan

    M Hiasa

  7. Research Division, Chugai Pharmaceutical Co, Ltd, Shizuoka, Japan

    N Kimura, Y Kikuchi, A Sakamoto, K Habu, M Endo & H Yamada-Okabe

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  1. A Ikegame
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Correspondence to S Ozaki.

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Author Contributions

AI and SO designed and conducted in vitro and in vivo studies, and prepared the manuscript. DT and KI conducted flow cytometric SP analysis. TH, SF, SN, HM, AN, KK, KT and MA provided clinical samples. KW and MH contributed to in vivo studies. HO generated the diabody. TM supervised the project.

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Ikegame, A., Ozaki, S., Tsuji, D. et al. Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors. Leukemia 26, 2124–2134 (2012). https://doi.org/10.1038/leu.2012.78

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