Genetic recombinations between c-myc and Ighμ as precursors for recombinations between c-myc and Ighα in BALB/c plasmacytomas

Abstract

In this paper we present evidence that primary plasmacytomas harboring a balanced chromosomal translocation t(12;15) may consist of a mosaic of neoplastic clones of tumor cells, in which some of the clones are derived from common progenitors by large additional deletions which alter or 'remodel' the fine structure of the t(12;15) on the c-myc-deregulating chromosome. This finding is based on the molecular analysis of the t(12;15) in three plasmacytomas, TEPC 1194, PCT 4127 and PCT 4132, in which primary clones of tumor cells with recombinations between the Ig heavy-chain (Igh) μ locus (Ighμ) and c-myc were found to be related to secondary clones of tumor cells with recombinations between the Igh α locus (Ighα) and c-myc. Clonal relatedness was based on unique junction fragments between Sμ and c-myc that were found to be identical in Ighμ/c-myc and Ighα/c-myc breakpoint regions. Sμ/c-myc breakpoints with adjoining sequences can thus be used as clonotypic markers, providing molecular fingerprints for the evolution of precursor cells with Ighμ/c-myc recombinations into progenitor cells with Ighα/c-myc recombinations. We propose that aberrant isotype switch recombination or illegitimate rearrangement in switch regions converts Ighμ/c-myc rearrangements, which are found very rarely in established plasmacytomas, into Ighα/c-myc rearrangements, which are present in about 80% of plasmacytomas with t(12;15). Remodeling of the t(12;15) results in closer juxtaposition of c-myc to the 3'-Cα locus control region and probably in enhanced transcription of c-myc. We suggest that remodeling of c-myc- deregulating rearrangements constitutes a novel progression mechanism in malignant B-cell development.