| The ability to genetically engineer mice has opened unprecedented opportunities to study basic biology in vivo and to generate animal models for human diseases. This is true for both fields of cancer and immunology, where today mouse models help us understand disease pathogenesis, identify molecular targets for drug development, and test novel therapeutic approaches. Several transgenic models for B lymphocyte tumors have been developed, but no engineered model has been able so far to faithfully reproduce the phenotype of late stage B cell tumors such as germinal center (GC) lymphomas and multiple myeloma (MM).; To address this challenge, we took advantage of the B cell-restricted, GC-specific, process of somatic hypermutation (SH). SH is the mechanism which modifies the DNA sequence to enhance the affinity of antibodies against antigens, it is induced by antigenic stimulation (e.g. vaccination), and it is active only late in B cell development. We generated transgenic mice bearing stop-inactivated oncogenes. These were engineered in a way to be unlocked sporadically by SH, actually mimicking what happens in a portion of human B cell tumors, where translocation breakpoint studies strongly suggest an active role of SH in causing oncogenic chromosomal translocations.; One of these mice, with a MYC transgene, develops a phenotype in all similar to the human plasma cell tumor MM, with clonal antibody-secreting plasma cells residing in the bone. Another one, with a BCL6 transgene, develops GC lymphomas. Because SH is what turns on the oncogene, and since SH is induced in response to antigen challenge, we predicted that vaccinating MYC transgenic mice would increase the chances to activate the oncogene and that the resulting neoplasia would be antigen-specific. In agreement with this prediction, we were able to induce antigen-specific gammopathies.; We propose that these mice may represent a suitable model system to investigate the role of antigen stimulation in B cell tumorigenesis. |
