General discussion The adaptive immune system is characterized by its ability to mount specific responses against pathogens, mediated by lymphocytes and antigen-presenting cells. B cells produce antibodies and use B-cell receptors (BCR, also termed antigen receptor or immunoglobulin) to recognize and eliminate pathogens, damaged or non-self cells; these responses are called humoral immunity. T cells also use specific receptors– T-cell receptors (TCR) to eliminate foreign antigens in responses that constitute the cellular adaptive immunity. To generate a diverse array of antigen receptors, a sophisticated system of somatic gene recombination called V(D)J recombination is employed, in which the V (variable), D (diversity), and J (joining) segments of the immunoglobulin chains are reorganized to form a new sequence. The process of gene recombination, specific for B and T cells, is initiated by the recombination activating gene 1 and 2 (RAG1/2) endonuclease complex, introducing DNA breaks at recombination signal sequences (RSS), specific sequences that flank the recombining gene segments within the immunoglobulin (Ig) and Tcr loci. During V(D) J recombination additional variability at junctions of coding segments is introduced by terminal deoxynucleotidyl transferase (TdT), further increasing receptor diversity1. However, due to the introduction of DNA breaks during the V(D)J recombination, this intricate system poses a risk to genome integrity. The stringent and well-orchestrated control of the RAG1/2 complex during B-cell development ensures minimization of the unintended damage caused by the RAG1/2 complex while allowing the formation of functional BCR necessary for B-cell maturation. Acute lymphoblastic leukemia (ALL) is a type of blood cancer characterized by the rapid expansion of malignant B- or T-cell precursors. Genomic instability is the hallmark of ALL, including the ETV6-RUNX1, BCR-ABL1, and E2A-PBX1 translocations2. Footprints of RAG1/2 activity, such as insertion of N-nucleotides, or presence of sequences resembling RSS, were found in the proximity of genomic lesions in both mouse and human B-cell malignancies, including ALL. This implicates aberrant RAG1/2 targeting and/or activity in the development of lymphoid malignancies. A thorough understanding of the mechanisms governing the (mis)-regulation and the (mis)-targeting of RAG1/2 within the genome may offer insights into the molecular pathogenesis of pre-B-cell malignancies. 168 | Chapter 7
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