Immunoglobulin heavy-chain switching in pre-B leukaemias

Immunoglobulin gene expression is initiated in pre-B cells by rearrangements of heavy-chain variable genes V, D and J, for transcription together with the constant region gene C mu (refs 1-7). The subsequent joining of light-chain V-J genes in the kappa or lambda families leads to formation of complete IgM molecules, which are then expressed on the surface of B cells. Heavy-chain isotype switching has been thought to occur later and to involve CH gene rearrangement via deletion of DNA between a switch site 5' to C mu and a switch site 5' to the downstream C gamma, C epsilon or C alpha gene expressed by a mature plasma cell. On the other hand, isotype switching has been seen in human pre-B-cell leukaemias and in a murine pre-B-cell line before light-chain gene rearrangements and without C mu gene deletion. To explore further the isotype switching in pre-B cells, we used monoclonal antibodies in immunofluorescence assays to allow unambiguous assignment of the heavy-chain isotypes expressed by individual leukaemic cells in 11 pre-B-cell leukaemias. Switching in these leukaemic clones invariably led to expression of gamma 1 heavy-chain and kappa light-chain determinants, occasionally together with gamma 4 and alpha. These results indicate a nonrandom order for heavy-chain isotype switching and for light-chain isotype expression, and also suggest that a mechanism exists for coordinating the two events.