Regulation of Genome Rearrangement Events during Lymphocyte Differentiation

Analyses of A-MuLV transformed cell lines have provided fundamental insights into the molecular mechanisms which control the rearrangement events leading to the expression of specific antigen receptor genes. These studies have clearly indicated that tissue-specific, developmental stage-specific, and allelically excluded assembly of Ig H and L chain and TCR variable region genes are very strictly regulated processes and, furthermore, that this regulation probably is effected at the level of the accessibility of the individual sets of V gene segments to a common recombinase. More preliminary studies have also suggested that accessibility targeting may be involved in the regulation of directed Ig H chain class-switch recombination events. Currently, we do not understand the nature of "accessible" DNA sequences and we have little understanding of the molecular mechanisms by which Ig (and potentially TCR) chains mediate the regulation of specific recombination events by signaling changes in the accessibility of the various loci. However, an ideal model system for the analysis of these questions is currently available in the form of A-MuLV transformed pre-B cell lines which, in a properly regulated fashion, undergo all of the various recombination events associated with the pre-B stage of B cell differentiation.