title: 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.
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.
authors.affiliation: Multiple Myeloma Research Laboratory (MMRL), Singapore Health Services (SingHealth) Research Facilities, Singapore, Singapore.
authors.forename: W Y K
authors.initials: WY
authors.lastname: Hwang
authors.forename: C A
authors.initials: CA
authors.lastname: Gullo
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: C K
authors.initials: CK
authors.lastname: Poh
authors.forename: S C
authors.initials: SC
authors.lastname: Tham
authors.forename: G
authors.initials: G
authors.lastname: Cow
authors.forename: M
authors.initials: M
authors.lastname: Au
authors.forename: E W E
authors.initials: EW
authors.lastname: Chan
authors.forename: G
authors.initials: G
authors.lastname: Teoh
mesh_terms: D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D042822:Genomic Instability; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
chemical_list: D019013:CD40 Antigens; D007143:Immunoglobulin Heavy Chains; D023201:CD40 Ligand; D015847:Interleukin-4; D004247:DNA; D003564:Cytidine Deaminase