AID-Dependent Activation of a MYC Transgene Induces Multiple Myeloma in a Conditional Mouse Model of Post-Germinal Center Malignancies

• Published in: Cancer cell Vol. 13; no. 2; pp. 167 - 180
• Main Authors: Chesi, Marta, Robbiani, Davide F., Sebag, Michael, Chng, Wee Joo, Affer, Maurizio, Tiedemann, Rodger, Valdez, Riccardo, Palmer, Stephen E., Haas, Stephanie S., Stewart, A. Keith, Fonseca, Rafael, Kremer, Richard, Cattoretti, Giorgio, Bergsagel, P. Leif
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2008
• Subjects: AICDA (Activation-Induced Cytidine Deaminase); Animals; Antigens, Neoplasm - immunology; Cell Proliferation; CELLBIO; Codon, Terminator - genetics; Cytidine Deaminase - metabolism; Disease Models, Animal; Disease Progression; DNA Mutational Analysis; Drug Screening Assays, Antitumor; Gene Expression Profiling; Germinal Center - pathology; Humans; Immunization; Mice; Models, Biological; Molecular Sequence Data; Multiple Myeloma - enzymology; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Organ Specificity; Paraproteinemias - pathology; Plasma Cells - enzymology; Plasma Cells - pathology; Protein Engineering; Proto-Oncogene Proteins c-myc - genetics; Somatic Hypermutation, Immunoglobulin - genetics; Transgenes - genetics; CELLBIO
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2008.01.007

By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B cells of Vk ∗MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk ∗MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA, and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma.