CHROMOSOME TRANSLOCATIONS AND IG GENES IN HUMAN LEUKEMIA

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In connection with recent hypotheses concerning carcinogenic mechanisms at the level of the genome, it has been suggested that certain chromosomal translocations frequently observed in human lymphoid neoplasms may involve immunoglobulin genes and bring transcriptionally active portions of these genes into juxtaposition with other segments of the genome (oncogenes?), leading to their activation and neoplastic transformation. We have now completed planned studies that extend our previous observations with the more common 8;14 translocation to the variant 8;22 and 2;8 translocations in the Burkitt lymphoma. We have demonstrated that in both of these variant circumstances, the c-myc oncogene remains on the 8q+ chromosome and that the immunoglobulin light chain gene translocates to this chromosome 8 resulting in transcriptional activation of the c-myc oncogene. This showed that the activating effect of the immunoglobulin gene could occur whether it was located on the 5' side or the 3' side of the c-myc oncogene and also that rearrangement of the oncogene itself was not required. We are now extending these studies to B-cell neoplasms with characteristic t(11;14) (q.13; q.32) and t(14;18) (q.32; q.21)chromosome translocations. Our initial results indicate that the breakpoint on chromosome 14 involves the immunoglobulin heavy chain locus, and have suggested that as yet unidentified proto-oncogenes (bc1-1, bc1-2) may be translocated from the long arms of chromosomes 11 and 18, respectively to the heavy-chain locus on chromosome 14 with rearrangement of the postulated proto-oncogenes. We\have also shown that the breakpoint on chromosome 22 in chronic myelogenous leukemia (CML) is distal to the constant region of the lambda light-chain locus and so is different from the breakpoint seen in the 8;22 variant of the Burkitt lymphoma. Preliminary data suggests that unlike CML, the lamda light-chain gene may be involved in the pathogenesis of acute lymphocytic leukemia (ALL) with the Philadelphia chromosome. (M)