We have been studying the molecular mechanisms governing B cell differentiation and neoplasia in tumors that arise in transgenic mice which overexpress the myc oncogene under transcriptional regulation of mutant or wild-type immunoglobulin heavy chain enhancer constructs. Normally, the heavy chain enhancer functions only in B cells; however, the mutations relieve constitutive suppression of the enhancer and allow it to activate myc gene expression in non-B cells as well as B cells. The strains with wild-type enhancer constructs invariably succumb to pre-B or mature B cell lymphomas while the transgenic mice with the mutant enhancers get tumors encompassing a wider spectrum of hematopoietic differentiation including pro-B, pre-T, T, and macrophage tumors in addition to pre-B and B cell tumors. In order to identify genes that collaborate in transformation with the inappropriately expressed myc gene, we use a PCR-based assay capable of quantifying expression of 20 candidate oncogenes. Tumors arising in these mice have also been used to investigate normal molecular events governing B cell differentiation. Cell surface expression of the pre-B-cell stage specific genes lambda-5 and VpreB has been found to correlate with down-regulated RAG-1, a crucial part of the multi-enzyme VDJ recombinase complex. Cells with this phenotype are unable to catalyze F(D)J recombination. These cells may represent an important stage in which pre-B cells undergo allelic exclusion at the immunoglobulin heavy chain locus.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Intramural Research (Z01)
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