Cross-lineage gene rearrangements in human leukemic B-precursor cells occur frequently with V-DJ rearrangements of IgH genes

Gene configurations of immunoglobulin (Ig), T-cell antigen receptor (TCR) beta chain, and T-cell rearranging gene gamma (TRG gamma) were studied in human B-precursor lymphoblastic leukemic cells. These cells were phenotypically classified into three developmental stages (stages II through IV) according to Nadler's criteria. All of them showed the Ig heavy chain (IgH) gene rearrangement, and 67% of the cells in stage IV had the rearranged TRG gamma, albeit seldom in other stages. We further analyzed IgH gene rearrangements in detail using upstream to DH (diversity region of IgH) region probe to distinguish DJ from V-DJ recombination. All dual genotyped cells in each stage except one case in stage II showed the V-DJ rearrangements. This suggests the cross- lineage involvement of the putative recombinase, particularly in the process of V-DJ rearrangements. We next examined the transcriptional status of Ig genes as an indirect reflection of the accessibility of these genes to the recombinase. Properly spliced IgH transcripts of normal size were observed in stage IV and surface Ig positive stage, but not in stage II nor III. However, IgH transcripts of aberrant sizes were seen in stage II, III, and also IV. Cross-lineage gene rearrangements were shown to occur frequently when normally spliced IgH gene begins to be transcribed or just before this. These findings may implicate that V-DJ or V-VDJ gene rearrangements forming functional IgH genes, induce frequently TCR or TRG gene rearrangements. We propose these dual genotypes are different in origin from those observed in stem cell leukemia.