2 Role of RAG1 and RAG2 in B-cell development | 39 instead, they accumulate in bone marrow, crowding out the normal cells. The presence of mutations, translocations, or other genomic abnormalities is a hallmark of ALL. There are several hypotheses regarding the underlying cause and mechanisms that give rise to B-ALL, including the so-called “2 hit theory” postulating that for the development of cancer, at least 2 different mutations are needed: suggests that two separate genetic mutations are necessary for the development of cancer. The first hit, often a dominantly inherited predisposition to cancer may entail a germline mutation. The second hit occurs when the other copy of the gene also becomes mutated, either through environmental factors (like exposure to carcinogens) or random errors in DNA replication. This second mutation is usually acquired later in life. This model helps explain why certain individuals with a hereditary predisposition to cancer may be more susceptible to developing the disease and why cancer development often involves multiple genetic alterations194. The most prevalent chromosomal lesion in ALL is the t(12;21)(p13;q22) translocation, creating the ETV6/RUNX1 fusion gene (also known as TEL/AML1)195. This translocation is present in 25% of the childhood ALL cases196. The detection of ETV6/RUNX1 fusion gene presence in the neonatal blood suggests that the first event takes place in utero. Moreover, the ETV6/ RUNX1 fusion gene is present in 1-5% of newborns, but the actual incidence of ETV6/ RUNX1+ B-ALL is much lower (0.0001%), suggesting that a secondary hit is needed for the malignant transformation and the development of clinically relevant B-ALL197. The ETV6/ RUNX1 gene product was associated with increased levels of reactive oxygen species (ROS)198. It has been proposed that the ROS-mediated formation of DSBs may be one of the sources of genomic instability, delivering the secondary hits199. Because RAG1/2 is a source of DBSs in progenitor B cells, its dysregulation was also suspected to be a significant source of secondary mutations. Exome and whole-genome DNA sequencing of ALL cells carrying ETV6/RUNX1 translocation revealed the presence of RSS motifs near the translocation breakpoints, as well as the presence of N-nucleotides at the junctions, a typical signature of RAG activity97. Inactivating deletions in PTEN are detected in 8% of childhood T-ALL cases. The breakpoints in PTEN inactivation deletions were found to be flanked by cRSS and the presence of N-nucleotides inserted in between the breakpoints, implicating aberrant RAG1/2 activity107,200. Besides the ETV6/RUNX1+ cytogenetic subgroup, hyperdiploid B-ALL cases revealed recurrent RAG-mediated copy number alterations (CNAs) in genes including PAX5, IKZF1, and ETV6. In addition, hyperdiploid B-ALL shows frequent mutations in receptor tyrosine kinase (RTK)-RAS pathways and mutations affecting histone modifiers201. The BCR-ABL1 translocation, or the so-called Philadelphia chromosome-positive ALL (Ph+ALL), constitutes approximately 5% of childhood ALL cases and 20% of adult ALL cases202. In adult cases of B-ALL carrying the BCR-ABL1 t(9;22) translocation, the presence of cRSS and N-nucleotides was reported in the breakpoint regions, as well as abundant RAG binding in the breakpoint proximity203.
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