Immunoglobulin gene rearrangement is fundamental to the development of lymphocytes. Understanding the generation of these cells and the means by which they acquire specific antigen receptors remains one of the central issues in immunology. Abelson virus transformed pre-B cells have been extremely useful for investigating the molecular events controlling immunoglobulin gene rearrangement. Despite the power of this approach, one important feature has been missing from this model: the ability to manipulate the differentiation of the cells in a predictable and controllable fashion. We have overcome this obstacle by using pre-B cells transformed with temperature sensitive Abelson virus. When these cells are incubated at the nonpermissive temperature, light chain gene rearrangement is activated in a high percentage of the cells within one to four days. We will use the temperature sensitive pre-B transformants to ask three questions. 1. Does the pre-B to B cell transition occur in the temperature sensitive transformants and is it regulated by immunoglobulin molecules? The high frequency of light chain rearrangement observed in the temperature sensitive transformants may reflect activation of this single event or activation of the B cell differentiation program. We will examine expression of differentiation markers to distinguish between these two possibilities and test the role of immunoglobulin proteins in stimulating differentiation of the cells. 2. Are rearrangement of kappa and lambda genes and RS sequences regulated or stochastic processes? We will use a series of time course experiments to determine if rearrangements of kappa, lambda and RS are related temporally. The relationship between transcriptional activity, changes in chromatin structure and gene rearrangement will be examined. 3. What genes are upregulated during light chain rearrangements? Differential display will be used to identify sequences that are expressed at high levels when light chain gene rearrangement is activated. A long range goal of these experiments is to identify genes that are important for light chain rearrangement.
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