Molecular processes during human B-cell differentiation

In this thesis three main subjects are discussed. The first subject (Chapter 2) focusses on the human IGL locus. Two aspects of the IGL gene locus are discussed, i.e. isotype rearrangements in B-ee!! malignancies and the two human IGL light chain polymorphisms. The second subject is the central theme of this thesis and deals with the regulation of Ig light chain gene recombinations (Chapter 3). Several types of B-cell malignancies were used as clonal "single cell" model to study rearrangement patterns of Ig light chain genes. Processes that might influence regulation of Ig light chain rearrangements, including the degree of order of Ig light chain gene rearrangements, allelic exclusion, and somatic mutations followed by receptor revision, are studied and discussed. Oncogenic recombinations in B-cell malignancies are discussed Chapter 4. First, the considerations for the development of split -signal FISH for chromosome aberrations are described. The general principle of split-signal FISH was illustrated in translocations involving the MLL gene, which has a large number of partner genes. Furthermore, the influence of translocations involving the E2A gene, on antigen receptor gene rearrangement patterns in pre-B-ALL is discussed. Finally, split-signal FISH for the five most important translocations is summarized. The General Discussion (Chapter 5) contains the main and integrated conclusions together with directions for future research.

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