Antigen receptor genes as molecular markers of lymphoid neoplasms.

Molecular analysis of human lymphoid neoplasms is markedly altering our concepts of their pathogenesis and classification. Before the era of recombinant DNA, major advances were provided by the investigation of cell surface antigens representing maturational stages of B or T cells (1). Despite the generation ofmany antibodies to B and T cell antigens, it was still impossible to classify the cellular type of some lymphoid neoplasms. This inadequacy frequently reflected the admixture of large numbers of nonneoplastic cells within lymphomatous tissue. Such cells could not be distinguished inasmuch as virtually all the lineageassociated markers were present on normal as well as malignant cells. In other instances, leukemias represented stages of development prior to the expression of lineage-restricted antigens. Frequently, it was even impossible to determine whether a lymphoid neoplasm was of clonal origin. The rearrangements of DNA which assemble the antigenspecific receptor genes in B or T cells provide the necessary tools to overcome many of these limitations. The immunoglobulin (Ig) and T cell receptor (TCR)1 genes are composed of multiple, separated gene subsegments within their germline or embryonic state. During lymphoid development a DNA recombination process assembles the components of Ig genes in B cells or TCR genes in T cells (2-4). Most of our knowledge concerning these genes including their ordered sequence ofDNA rearrangements, mechanisms of recombination, somatic mutation, alternative RNA splicing, and transcriptional regulation was gleaned from established lymphoid neoplasms. In return, these contributions to basic biology have paid dividends by resolving uncertainties concerning the lineage commitment, clonality, stage of development, and pathogenesis of leukemias and lymphomas. Specifically, Ig and TCR gene rearrangements create DNA-level markers unique to each individual cell. This sensitive and specific molecular fingerprint is capable of identifying a clonal expansion of B or T cells. Moreover, a developmental hierarchy for both Ig and TCR gene rearrangements occurs during early B and T cell maturation, providing new means ofcategorizing neoplasms. Most importantly, unanticipated rearrangements ofIg and TCR loci have been discovered which directly contribute to the ma-