Molecular genetics of B- and T-cell neoplasia

Specific chromosomal translocations are involved in more than 80% of human B-cell neoplasms. In all these cases the neoplastic phenotype is apparently the consequence of reciprocal chromosomal translocations involving the loci for human immunoglobulin (Ig) chains and either well described cellular proto-oncogenes or putative proto-oncogenes. The juxtaposition of the proto-oncogenes to the Ig loci results in their transcriptional deregulation, because of their proximity to genetic elements within the Ig loci capable of activating gene transcription in cis over considerable chromosomal distances. Sequence analysis of the translocation breakpoints has provided important insights concerning the molecular mechanisms involved in chromosome translocation in B-cells. It appears that the reciprocal translocations contributing to B-cell neoplasia are catalyzed by the same enzymes that are involved in physiological Ig gene rearrangements. The analysis of human B-cell leukemias and lymphomas has also provided considerable information concerning the possible scenarios for B-cell neoplastic transformation. It is clear that the Epstein-Barr virus does not play a direct role in neoplastic transformation, but it may contribute by increasing the number of B-cells at risk of developing chromosome translocations during Ig gene rearrangements. Cytogenetic and molecular genetic analysis of T-cell malignancies is beginning to provide a very similar scenario for neoplastic transformation. The locus for the alpha chain of the T-cell receptor is directly involved, and it apparently juxtaposes to proto-oncogenes or to putative proto-oncogenes leading to their transcriptional deregulation. It seems quite likely that the enzyme system involved in rearrangements of the genes for the T-cell receptor plays a crucial role in the causation of these chromosomal translocations. Thus, the genetic basis of many human B- and T-cell neoplasms may be quite similar. For the future, the challenge resides in trying to characterize specifically the role of both old and new proto-oncogenes in B- and T-cell proliferation, normal and neoplastic.