AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies.
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.
Chesi
Marta
M
Comprehensive Cancer Center, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. chesi.marta@mayo.edu <chesi.marta@mayo.edu>
Robbiani
Davide F
DF
Sebag
Michael
M
Chng
Wee Joo
WJ
Affer
Maurizio
M
Tiedemann
Rodger
R
Valdez
Riccardo
R
Palmer
Stephen E
SE
Haas
Stephanie S
SS
Stewart
A Keith
AK
Fonseca
Rafael
R
Kremer
Richard
R
Cattoretti
Giorgio
G
Bergsagel
P Leif
PL
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D049109:Cell Proliferation; D018388:Codon, Terminator / Q000235:genetics; D003564:Cytidine Deaminase / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D009928:Organ Specificity; D010265:Paraproteinemias / Q000473:pathology; D010950:Plasma Cells / Q000201:enzymology / Q000473:pathology; D015202:Protein Engineering; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D019076:Transgenes / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000951:Antigens, Neoplasm; D018388:Codon, Terminator; D016271:Proto-Oncogene Proteins c-myc; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase