Translocation Remodeling in the Primary BALB/c Plasmacytoma TEPC 3610 Alexander L. Kovalchuk, 1 Arif Esa, 2 Allen E. Coleman, 1 Sung S. Park, 1 Thomas Ried, 3 Christoph C. Cremer, 2 and Siegfried Janz 1 * 1 Laboratory of Genetics, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 2 Institute of Applied Physics, University of Heidelberg, Heidelberg, Germany 3 Genetics Department, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Myc-activating chromosomal 12;15 translocations, the hallmark mutations of inflammation-induced BALB/c plasmacytomas, have recently been shown to undergo remodeling by isotype switch-like genetic recombinations that remove  180 kb of immunoglobulin heavy-chain sequence in the vicinity of the rearranged, expressed Myc gene. Here we combine cytogenetic data on the 12;15 translocation (SKY and FISH) with the molecular analysis of key junction sites (long-range PCR followed by DNA sequencing) to demonstrate that translocation remodeling occurred as an infrequent, stepwise, and disomic tumor progression event in the tetraploid, fully transformed, and transplantable plasmacytoma TEPC 3610. This result was used, in conjunction with previously obtained molecular data on five other primary plasmacytomas, to devise a hypothesis that predicts that the selective pressure to undergo translocation remodeling may be predetermined by the location of the break site in Myc. The pressure may be low if the break occurs 5' of the normal promoter region of Myc, but it may be considerably stronger if the break occurs 3' of the Myc promoter. Published 2001 Wiley-Liss, Inc. † INTRODUCTION G-banding of tumor metaphase cells established more than 20 years ago that the great majority ( 90%) of malignant plasma cell tumors (plasma- cytomas) that develop in genetically susceptible BALB/c mice harbor a consistent cytogenetic aber- ration, the chromosomal 12;15 translocation (Ohno et al., 1979). The T(12;15) generates an enlarged chromosome 12 (hereafter referred to as derivative 12 or der 12) and a reduced chromosome 15 (here- after referred to as derivative 15 or der 15). It soon became clear that the translocation occurs as a reciprocal genetic exchange that juxtaposes the im- munoglobulin heavy-chain gene cluster, IgH, on chromosome band 12F1 to the Myc proto-oncogene on chromosome band 15D2. Subsequent molecular studies revealed that the translocation results in- variably in the deregulated expression of Myc (Shen-Ong et al., 1982), a key oncogenic event in BALB/c plasmacytomagenesis (Potter et al., 1992). The most recent methodological breakthrough in the continuing elucidation of the T(12;15) is marked by the development of PCR methods for the detection of 12;15-typical junction fragments between IgH and Myc. Since its inception, PCR analysis has been used to demonstrate that the translocation is a very early, if not initiating, onco- genic step during plasmacytoma development (Janz et al., 1993), that the fine structure of trans- location differs between fully transformed plasma- cytomas and their premalignant precursors (Mu ¨ ller et al., 1994), that translocated cell clones are capa- ble of migrating into different tissues (Mu ¨ ller et al., 1997), and that the propensity to undergo translo- cation is not correlated with the genetic suscepti- bility to plasmacytoma development (Mu ¨ ller et al., 1996; Roschke et al., 1997) . These findings have contributed significant new insights into the T(12; 15) and have supported the proposal that this trans- location should be considered a uniquely valuable model system for the better understanding of the multitude of oncogene-activating chromosomal translocations that occur in leukemias, malignant lymphomas, and multiple myelomas in humans. Molecular analysis of the fine structure of the T(12;15) by the most reliable PCR method avail- able today, long-range PCR (Kovalchuk et al., 2000), led to the realization that plasmacytomas that are typically characterized by genetic recom- binations between Myc and the most distal locus of the IgH gene cluster, C, can in fact be derived from precursors that are distinguished by recombi- nations between Myc and the most proximal locus Alexander L. Kovalchuk, Arif Esa, and Allen E. Coleman contrib- uted equally to this work. *Correspondence to: Dr. Siegfried Janz, Laboratory of Genetics, National Institute of Cancer, Building 37, Room 2B10, Bethesda, MD 20892. E-mail: sj4s@nih.gov Received 9 August 2000; Accepted 7 September 2000 Published online 11 January 2001 GENES, CHROMOSOMES & CANCER 30:283–291 (2001) Published 2001 Wiley-Liss, Inc. † This article is a US Government work and, as such, is in the public domain in the United States of America.