Unexpected consistent involvement of V beta gene segments in inappropriate T-cell receptor beta gene rearrangements occurring in B-lineage acute lymphoblastic leukemias.
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.
Dombret
H
H
Laboratory of Molecular Hematology, Saint-Louis Hospital, Paris, France.
Loiseau
P
P
Bories
J C
JC
Sigaux
F
F
D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D002051:Burkitt Lymphoma / Q000235:genetics*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000032:analysis / Q000737:chemistry; D017353:Gene Deletion; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
D015342:DNA Probes; D004273:DNA, Neoplasm