Carolyn K . Goldman , Philip Leder , And

The maturation of a pre-B cell to an immunoglobulin (Ig)-bearing B cell requires an effective recombination of a light chain variable (VL) 1 and joining (JL) gene segment (1-11). Man uses both light chain gene classes appreciably, expressing K light chain in -60% and ~ light chain in 40% of mature B cells. Despite their nearly equal usage, however, the rearrangement of human Ig light chain genes may occur in a preferential order in which K gene rearrangements precede those of 2~ (12-15). Specifically, we observed that K-bearing B cell lines or leukemias had retained their genes within the germ line configuration, whereas comparable ?~-bearing B cells had no remaining germ line K genes (12). In addition, other leukemic lymphocytes representing precursor stages of B cell development deleted their K genes, whereas their ~ genes remained untouched in the germ line state (15). These surprising findings, which suggested a sequential order for light chain gene rearrangements, were observed on either transformed B cell lines or leukemic lymphocytes. Thus, the question arose as to whether this apparent ordering of light chain gene rearrangement was a normal, functional event or simply a consequence of the transformation process. This uncertainty required investigation, as the specific chromosomal translocations that occur in malignant human B cells frequently involve the Ig-bearing chromosomes (heavy chain genes are on chromosome 14, K light chain genes are on chromosome 2, and ?~ light chain genes are on chromosome 22) (16, 17). Such translocations might well occur within the Ig gene loci and could themselves produce some of the gene recombinations and deletions we observed. To resolve this issue, we isolated the circulating h-bearing B cells from a normal individual and determined the state of their collective K and ~ genes. Over 95% of the K genes in these nontransformed ~ B cells were no longer in their germ line form, with the majority (60%) being deleted and the remainder being present but in a rearranged state. Furthermore, the incidence of K gene deletion was greater in long-term ?~ B cells than in these normal ~ B cells or freshly transformed ~ B cell lines. Such K gene deletions may therefore result from a second mechanism that eliminates aberrantly rearranged genes and their products. Thus, despite the nearly equal usage of K and ~k light-chain genes in man, there appears to be a sequential order to their rearrangement during normal B cell ontogeny in which t¢ rearrangements precede those of the ~ genes.