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

• Published in: Leukemia Vol. 20; no. 4; pp. 715 - 723
• Main Authors: HWANG, W. Y. K, GULLO, C. A, SHEN, J, POH, C. K, THAM, S. C, COW, G, AU, M, CHAN, E. W. E, TEOH, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.04.2006; Nature Publishing Group
• Subjects: Abnormalities; Apoptosis; Biological and medical sciences; CD40 antigen; CD40 Antigens - immunology; CD40 Ligand - pharmacology; Cell activation; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Chains; Chromosome 14; Chromosome Aberrations; Chromosome translocations; Class switching; Cytidine deaminase; Cytidine Deaminase - biosynthesis; Cytidine Deaminase - drug effects; Cytokines; Decoupling; Deoxyribonucleic acid; DNA; DNA - biosynthesis; DNA - drug effects; DNA damage; DNA repair; Evolution; Genomic Instability; Heavy chains; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulin Heavy Chains - drug effects; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - immunology; Immunoglobulinopathies; Immunoglobulins; Immunopathology; Interleukin 4; Interleukin-4 - immunology; Interleukin-4 - pharmacology; Intermediates; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Recombination; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Stability; Tumor cell lines; Tumor cells; Up-Regulation; Singapore; Ku proteins; Myeloma; DNA repair; DNA protein kinase; Signal transduction; Interleukin 4; Immunoglobulinopathy; Lymphoproliferative syndrome; Established cell line; Mechanism of action; Human; Immunopathology; Heavy peptide chain; Immunoglobulins; Enzyme; Transferases; activation-induced cytidine deaminase; Cytokine; Malignant hemopathy; DNA double stand breaks; Protein kinase; DNA; Instability; Isotype switching; Genome
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404099

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.