40 | Chapter 2 The notion that there might be a causal relation between infectious diseases and the development of ALL is now more than 100 years old204. It has been observed that infants in highly sanitized environments in developed societies experienced delayed exposure to infections. As a result, when they did encounter these infections, their immune responses were prolonged and exaggerated, leading to significant collateral damage. On the other hand, early exposure to common infections reduced this risk. Systemic introduction of vaccination programs in early childhood significantly decreased the risk of childhood ALL, presumably by reducing the chronic infections and the responses they instigate205,206. Indeed, repeated exposure to inflammatory stimuli has been shown to drive RAG1/2 and AID, which did not only enhanced the genetic diversity within B cells but also facilitated the acquisition of genetic abnormalities, thus promoting the clonal evolution toward leukemia202. For instance, the detailed analysis of the breakpoints provides evidence that the chromosomal recombination in human B-cell malignancies may originate from the collaboration between RAG1/2 and AID207,208, though the expression of these 2 enzymes was thought to be strictly segregated and confined to specific developmental stages of the B-cell development10. Taken together, all these findings underscore the potential threat that V(D)J recombination, SHM, and CSR pose to B cells throughout their development and maturation and the need for tight regulation of these processes. Concluding remarks and future perspectives Next to the conceptual breakthroughs in the topic of gene recombination from several decades ago, also in recent years, important discoveries have been made, especially adding to our understanding of RAG1/2 binding, targeting, and regulation. It became clear that the gene recombination system evolved in a way that allows for the generation of a staggering diversity in antigen receptors, at the expense of the risk imposed by the generation and repair of DNA breaks. In lymphocytes these risks are mitigated by various regulatory mechanisms, protecting the stability of their genome. The DNA breaks generated by V(D)J recombination have important regulatory functions, activating DDR responses, which in return control the availability of their substrates. On the signaling level, ATM, p53, and NF-kB pathways, activated by the DSBs, seem to on one end converge towards the same effect – control of RAG1/2 endonuclease availability and the V(D)J recombination efficiency121,171,185,191, and at the same time branch out to influence many other cellular processes as well. The qualitative and temporal crosstalk between these pathways is not fully understood yet. The occurrence of genomic lesions resulting from the off-target V(D)J recombination and the RAG1/2 activity seems to be rare, despite the genome-wide binding of RAG1 and RAG2 in mouse lymphocytes71. In cell systems that are unable to repair the DSBs, the location of the off-target RAG-dependent DSBs can be studied in more detail and the
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