Continuing his studies on balanced chromosomal translocations deregulating the proto-oncogene c-myc in BALB/c plasmacytomas, Dr. Juergen R. Mueller performed a series of experiments on the migration of translocation-positive B cells in lymphoid tissues of mice in which he was able to document the trafficking of aberrant B cells between the Peyer's patches and into the lamina propria of the intestine. He could further show that treatment of plasmacytoma susceptible BALB/cAnPt mice with the isoprenoid plasmacytomagenic C19-isoalkane pristane (2,6,10,14- tetramethylpentadecane) induced proliferation and swift migration of B cells harboring translocations into the mesenteric lymph node, the spleen and the pristane-induced inflammatory granuloma (Blood 89, 291- 296, 1997). This result strongly suggested that normal mice may generate a large number of abnormal B cells with constitutive expression of c- myc. The same conclusion could apparently be reached by a newly developed in situ technique which allowed the detection of up to five distinct translocation-positive B-cell clones in a single Peyer's patch of a BALB/c mouse (Genes, Chromosomes & Cancer 20, 1 8, 1997). Dr. Alexander L. Kovalchuk extended his analysis of the fine structure of illegitimate genetic recombinations between Igh mu and c-myc in primary BALB/c plasmacytomas and was able to demonstrate unequivocally that recombinations between Igh mu and c-myc are the molecular precursors for a subgroup of plasmacytoma-typical recombinations between Igh alpha and c-myc (Curr. Topics Microbiol. Immunol. 122, 111-111, 1997). In addition, he developed new long template and high fidelity PCR methods and employed them to scrutinize various lymphoid tissues of IL-6 transgenic BALB/c mice in which he detected a surprisingly high frequency of unusual B cells containing illegitimate recombinations between Igh mu and c-myc. Pursuing the productive ongoing collaboration with Dr. Thomas Ried's laboratory, Mr. Allen E. Coleman employed spectral karyotyping (SKY) - a recently developed chromosome painting method for obtaining a multicolor spectral karyotype of the entire mouse chromosome complement (Nature Genetics 14, 312-315, 1996) - to uncover previously hidden chromosomal aberrations in a sample of ten established BALB/c plasmacytomas. He observed several hotspots of chromosomal aberrations involving Chrs 1, 2, 4, 12, 14 and X in that tumor sample and concluded that secondary chromosomal rearrangements may be important determinants of plasmacytoma progression in BALB/c mice. To evaluate the true significance of these cytogenetic aberrations for the development of plasmacytomas in BALB/c mice, primary tumors are currently being investigated by SKY. Another major project in our laboratory is directed at testing the long held, yet unproven, assumption that B-cell mutagenesis is a requisite companion of malignant B-cell transformation. To address this problem, Dr. Klaus Felix chose to employ two independent, recently developed, transgenic in vivo mutagenesis assays that are based on a phage lambda- derived lacI and a plasmid-derived lacZ reporter gene, respectively. For studying mutation frequencies on genetic backgrounds that are conducive for plasmacytoma research, it is necessary to backcross genes lacI and lacZ onto plasmacytoma susceptible BALB/cAnPt and plasmacytoma resistant DBA/2N mice. Dr. Felix, in conjunction with Mr. Kevin Kelliher, has almost accomplished that goal. The great potential of transgenic mutagenesis assays for determining mutant frequencies in B cells has already become apparent in pilot studies on the mutagenicity of pristane (Cancer Letters 113, 71-76, 1997) and small organosilicone compounds, as well as the mutagenic potency of activated phagocytes undergoing an oxidative burst.
