M.D. - Harvard University, 1963

Research Professor in Molecular and Cell Biology

NCI/NIH

Laboratory of Genetics, Division of Basic Sciences

National Cancer Institute

Building 37, Room 2B26

NIH, Bethesda MD 20892-4255

Telephone: (301)-496-5260

Fax: (301)-402-1031

E-mail: mushinsj@pop.nci.nih.gov

Research: Cell differentiation and Neoplastic Transformation .

BALB/c plasmacytomas, like rat immunocytomas and human Burkitt lymphomas, are characterized by constitutive expression of c-myc mRNA and protein. Most commonly, c-myc expression in plasmacytomas is dysregulated secondary to a chromosomal translocation in the vicinity of c-myc. A "variant" set of plasmacytomas have translocations far downstream of c-myc, in a region designated Pvt1. A few plasmacytomas demonstrate dysregulated c-myc expression but no sign of chromosomal abnormality. We have determined that at least two of these tumors have a retrovirus integrated upstream of c-myc, whose strong LTR enhancer drives the c-myc to constitutive expression, but the up-regulated c-myc expression in the others is not yet understood. Other fundamental facts that are not yet explained is why the c-myc and Pvt1 loci are the exclusive sites of genetic insults nor why the BALB/c strain of mice is uniquely sensitive to oil-induced plasmacytomagenesis. There may be a clue in our finding that B lymphoblasts from BALB/c mice have a defect in DNA excision repair, while repair is normal in lymphoblasts of DBA/2 mice that are not susceptible to oil-induced plasmacytomas. The repair defect is unusual because it is not coupled to a defect in RNA transcription, and it affects only c-myc, Pvt1, and the immunoglobulin genes (Salpha and Ckappa) that are commonly involved in plasmacytoma translocations.

Altered c-myc expression is essential, but it is not sufficient to achieve complete malignant transformation of plasma cells. v-abl, a protein tyrosine kinase oncogene, as a transgene or as a retrovirus, cooperates with c-myc to accelerate plasmacytoma induction. The ABL-MYC retrovirus, that we developed, overexpresses both v-abl and c-myc and is the most powerful plasmacytoma-inducing agent yet described. If ABL-MYC infects mice that have been immunized, 50% of the ensuing plasmacytomas produce myeloma proteins that react specifically with the immunogen. We have shown that this system is a useful alternative to hybridomas for producing monoclonal antibodies. Its potential in rabbit and human systems is now being explored. Other oncogenes, i.e., v-Ha-ras and v-raf, when constitutively expressed concomitantly with c-myc in retroviral vectors, rapidly induce plasmacytomas, but we are stlll searching for the altered gene that collaborates with c-myc in oil-induced tumors.

In the study of signal transduction in these cells, we are investigating protein kinase C (PKC), a multigene family of at least 11 structurally related enzymes that are important mediators of many forms of signal transduction. Using a variety of expression vectors, many of the PKCs have been overexpressed in fibroblasts, lymphocytic and myeloid cell lines, which has made possible the identification of specific functions and intracellular targets for the individual isoenzymes. In IL-6-dependent tissue culture lines of mouse plasmacytomas, activation of PKC-delta delays the induction of apoptosis that follows withdrawal of IL-6. We are studying the nature of PKC's involvement in plasmacytoma apoptosis, its involvement in cytoskeletal changes in cell shape, its relationship to the dysregulated myc in these tumors and its possible contribution to plasmacytomagenesis.