Unexpected consistent involvement of V beta gene segments in inappropriate T-cell receptor beta gene rearrangements occurring in B-lineage acute lymphoblastic leukemias

Abstract

T-cell receptor beta (TCR beta) gene rearrangements occur in a third of early B-cell acute lymphoblastic leukemias (ALLs). V, D, and J segments involved in these inappropriate rearrangements remain unknown and are of interest, both because partial D beta J beta and complete V beta D beta J beta recombinations occur at distinct stages of thymic maturation and because these rearrangements are regulated differently. We have therefore studied in detail seven cases of B-lineage ALL that show inappropriate clonal TCR beta gene rearrangements. Analysis of genomic DNA by Southern hybridization with C beta, J beta 1, V beta 8, and V beta 11 probes suggested the involvement of V beta segment in tumor cell rearrangements. A complete genomic library constructed from one case was screened with a C beta probe, and the TCR beta gene rearrangement was cloned and fully sequenced to show an out of frame V beta 2.2-J beta 2.6 recombination. TCR beta gene rearrangements occurring in other cases were further analyzed by polymerase chain reaction (PCR) using J beta and V beta primers and the resulting specific PCR products were sequenced. Evidence of clonal V beta rearrangements was obtained in all cases. These unexpected findings represent the first definitive demonstration that complete V beta(D beta)J beta rearrangements can occur in B-lineage cells and contrast with the previously reported lack of V beta(D beta)J beta rearrangement in B cells from V beta-J beta-C beta-E mu transgenic mice. In the context of increasing evidence that rearrangements are linked to transcription of unrearranged gene segments, these data prompt a search in B-lineage ALL cells for the presence of germline V beta transcripts whose deregulated expression may be linked to early transforming events.