Dr. Janz is a Visiting Scientist at the Laboratory of Genetics, National Cancer Institute. He obtained his M.D. and D.Sc. degrees from the University of Leipzig, Germany.
Chromosomal translocations that activate cellular proto-oncogenes comprise the central oncogenic step in the development of various forms of malignant lymphomas in man. So far, the mechanisms permitting interchromosomal, non-homologous recombinations have remained obscure, but we believe that genetically defined and manipulable animal models can provide useful tools to further our understanding of the origin, incidence, and functional consequence of illegitimate genetic recombinations. Our recent work has demonstrated the value of our principal experimental system, the induced plasmacytoma of the BALB/c mouse, to elucidate the role of aberrant recombinations in lymphomagenesis. Virtually all BALB/c plasmacytomas, in common with human Burkitt lymphoma and rat immunocytoma, are characterized by a disruption in or near the proto-oncogene c-myc which leads to constitutive expression of c-myc transcripts and protein. In BALB/c plasmacytomas, c-myc-activating genetic recombinations usually take the form of reciprocal chromosomal translocations t(12;15), t(6;15), and t(15;16) that juxtapose c-myc to genes of the immunoglobulin heavy-chain (IgH), kappa light-chain, and lambda light-chain loci, respectively. The predominant (~90%) c-myc-activating translocation is the t(12;15) in which the 5' region of c-myc is joined to an IgH switch region (S), in most of the tumors (28/35, 80%) so far studied to Salpha.
Time, frequency, and site of origin of the t(12;15) have been elusive for many years, until we showed that recombinations between c-myc and Salpha, which are indicative of the t(12;15), are a very early and surprisingly frequent step in plasma cell tumor formation in BALB/c mice. Our data suggested that i) the t(12;15) comprises the initiating oncogenic event in murine plasmacytoma- genesis, ii) a focal, rather than diffuse, expansion of t(12;15)-positive B-cells occurs at early preneoplastic stages, and iii) the t(12;15) is not rate-limiting in determining the overall tumor incidence (Janz, S. et al., Proc. Natl. Acad. Sci. USA 1993; 90:7361-7364). We extended our studies on preneoplastic recombinations in B-cells by comparing the fine structure of breakpoint regions on both the c-myc-activating chromosome (chr.) 12+ and the reciprocal chr. 15-. This investigation has resulted in the detection of a remarkable diversity of molecular structures of c- myc-activating recombinations in malignant plasma cells and their precursors. Our studies showed that i) some recombinations between c-myc and Salpha comprise precise, nearly reciprocal exchanges, ii) clonally related t(12;15)-positive microclones co-exist in the early preneoplastic stage of murine plasma cell tumor development, and iii) initial Salpha/c-myc breakpoint regions are intrinsically labile and characterized by a persisting instability of c-myc.
We then applied the methodological experience gained in the murine system to detecting recombinations between Ig switch regions and c-myc on both reciprocal products of recombination in human Burkitt's lymphomas and premalignant, peripheral B-cells obtained from HIV-infected homosexual men. We made the interesting observations that some of Ig/c-myc recombination- positive B-cells in HIV-infected individuals show an exceptional persistence and that recombinations in Burkitt's lymphomas are, in contrast to mouse plasmacytomas, remarkably precise. These data suggest differences in the mechanism of recombination between immunoglobulin genes and c-myc in distinct forms of B-cell lymphomagenesis and have implications for the nature of the B-cell in which these illegitimate recombinations occur. What is more, translocation breakpoint regions between immunoglobulin heavy-chain genes and c-myc could be subject to different modes of secondary mutational change: deletional remodeling in murine plasmacytomagenesis and base substitution mutagenesis in the development of human Burkitt's lymphoma.
Return to Laboratory of Genetics Home Page