Cancer Genetics - P. Leif Bergsagel

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

Submitted

The enzymatic activity of Activation-Induced Deaminase (AID) during the physiological processes of somatic hypermutation and class switch recombination occurring in germinal center B-lymphocytes has been implicated in oncogene activation in mature B-cell malignancies. By misdirecting the activity of 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, in contrast all Vk*MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. In one third of mice a more aggressive extramedullary form of myeloma develops and could be accelerated by immunization or through secondary signals including deliberate co-expression of Bcl2. 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 in man.