18 | Chapter 2 for the hypervariable (antigen-binding) part of the B-cell antigen receptor or antibody. The BCR diversity in developing B cells is further increased by terminal deoxynucleotidyl transferase (TdT), which catalyzes the addition of nucleotides to the 3’ end of DNA during the formation of the V(D)J junction. V(D)J recombination is a site-specific recombination process that takes place only at BCR/T-cell receptor (TCR) gene segments and occurs only in developing lymphocytes in a lineage-specific manner2. The process of gene recombination, coupled with the induction of junctional diversity, exhibits remarkable complexity, facilitating the creation of an extensive array of antigen receptors boasting millions of specificities, all while requiring modest gene coding capacity. However, the induction of DNA breaks necessary for recombination and the generation of billions of antigen receptors over an organism’s lifespan poses a substantial threat to genomic integrity and requires stringent fidelity mechanisms. T cells during their development also undergo RAG1/2-mediated gene recombination to express highly variable surface T-cell receptor (TCR) receptors alpha (a) and beta (b) chains, present in the majority of T cells, or gamma (g) and delta (d) chains present only in a minor population of T cells3,4. Though the order of TCR loci recombination differs from the order of BCR recombination, the molecular basis of the gene recombination is the same in B and T cells. Considering the scope of this thesis, only B-cell-related gene recombination processes, and their regulation, will be discussed. T-cell development and TCR recombination have extensively been reviewed elsewhere5–7. Aberrant V(D)J recombination has been demonstrated to be an underlying cause of several lymphoid malignancies, and therefore, the basic regulatory mechanisms safeguarding the genome integrity during V(D)J recombination are of great interest 8,9. To understand the pathogenesis of lymphoid malignancies, a deep knowledge of the inner workings of our immune system is needed. The following chapters summarize the current knowledge of the physiological B-cell development and gene recombination. B-cell development, gene recombination, and B-cell activation B-cell development All lymphocytes develop from common lymphoid progenitors (CLPs) that are derived from hematopoietic stem cells (HSCs). The commitment of CLPs to either B- or T-lineage is coordinated by a set of transcription factors10. Commitment to the B-lineage is at first instance mediated by early B-cell factor (EBF) and E2A transcription factors, and subsequently by Paired Box 5 (Pax-5)11. Commitment to the T-cell lineage is mainly orchestrated by Neurogenic locus notch homolog protein 1 (Notch-1) and GATA-3 transcription factors12 Pro-B cells are the earliest committed B-cell precursors. The early stage of B-cell development is characterized by the sequential recombination of the Ig loci (Figure 1). At the end of this stage, RAG1 and RAG2 proteins are expressed for the first time and the first
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