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Myeloma

Decoupling of normal CD40/interleukin-4 immunoglobulin heavy chain switch signal leads to genomic instability in SGH-MM5 and RPMI 8226 multiple myeloma cell lines

Leukemia volume 20, pages 715–723 (2006)Cite this article

Abstract

The processes mediating genomic instability and clonal evolution are obscure in multiple myeloma (MM). Acquisition of new chromosomal translocations into the switch region of the immunoglobulin heavy chain (IgH) gene (chromosome 14q32) in MM, often heralds transformation to more aggressive disease. Since the combined effects of CD40 plus interleukin-4 (IL-4) mediate IgH isotype class switch recombination (CSR), and this process involves DNA double strand break repair (DSBR), we hypothesized that CD40 and/or IL-4 activation of MM cells could induce abnormal DNA DSBR and lead to genomic instability and clonal evolution. In this study, we show that MM cell lines that are optimally triggered via CD40 and/or IL-4 demonstrate abnormal decoupling of IL-4 signal transduction from CD40. Specifically, CD40 alone was sufficient to trigger maximal growth of tumor cells. We further demonstrate that CD40 triggering induced both DNA DSBs as well as newly acquired karyotypic abnormalities in MM cell lines. Importantly, these observations were accompanied by induction of activation induced cytidine deaminase expression, but not gross apoptosis. These data support the role of abnormal CD40 signal transduction in mediating genomic instability, suggesting a role for the CD40 pathway and intermediates in myelomagenesis and clonal evolution in vivo.

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Acknowledgements

This work was supported by research grants from the National Medical Research Council (NMRC), Singapore (grant #s NMRC/0489/2000, NMRC/0758/2003 and NMRC/0734/2003); SingHealth (grant #s SU007/2001, SU008/2001, SU009/2001 and SU089/2003); and the Department of Clinical Research, SGH. We gratefully acknowledge the invaluable contributions of Ms Janice Chow and Ms Lim Lay Feng (Research Coordinators, MMRL) in proofreading this manuscript, and Ms Stephanie Fook Chong (Statistician, DCR) for statistical analyses.

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Author notes

  1. W Y K Hwang and C A Gullo: These authors have contributed equally and share first authorship in this paper.

Authors and Affiliations

  1. Multiple Myeloma Research Laboratory (MMRL), Singapore Health Services (SingHealth) Research Facilities, Singapore, Singapore

    W Y K Hwang, C A Gullo, J Shen, C K Poh, S C Tham, G Cow, M Au & G Teoh

  2. Department of Haematology, Singapore General Hospital (SGH), Singapore, Singapore

    W Y K Hwang, C K Poh & G Teoh

  3. Department of Clinical Research (DCR), SGH, Singapore, Singapore

    C A Gullo, J Shen & S C Tham

  4. Division of Research, SGH, Singapore, Singapore

    M Au

  5. Faculty of Medicine, National University of Singapore (NUS), Singapore, Singapore

    E W E Chan & G Teoh

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  1. W Y K Hwang
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Correspondence to G Teoh.

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Hwang, W., Gullo, C., Shen, J. et al. Decoupling of normal CD40/interleukin-4 immunoglobulin heavy chain switch signal leads to genomic instability in SGH-MM5 and RPMI 8226 multiple myeloma cell lines. Leukemia 20, 715–723 (2006). https://doi.org/10.1038/sj.leu.2404099

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