2 Role of RAG1 and RAG2 in B-cell development | 41 results can provide valuable insights into the off-target preferences of RAG1/2 recombinase (Ochodnicka-Mackovicova K et al, manuscript under consideration). In addition, understanding how cells maintain genome stability may provide insights into mutagenic processes in other cell types as well. The exploration of links between the B-cell-specific regulatory pathways and lymphoid malignancies may provide insights into novel targeted therapies. For instance, tyrosine kinase inhibitors, and specifically, ABL kinase inhibitors have already revolutionized the treatment of Philadelphia chromosome-positive B-ALL. The PI3K/AKT or mTOR pathway inhibitors (e.g., idelalisib or everolimus) showed promising results in inhibiting leukemia cell proliferation and enhancing the cytotoxic effects of chemotherapy209–211. Targeting the anti-apoptotic BCL2 (e.g. venetoclax) has demonstrated efficacy in inducing apoptosis and enhancing the sensitivity of leukemia cells to chemotherapy212. Inhibitors targeting JAK/ STAT proteins (e.g., ruxolitinib) may disrupt aberrant signaling and inhibit leukemia cell growth213,214. Immunotherapies targeting pre-B cell surface marker CD19, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers (BiTEs), redirect the patient’s immune system to selectively eliminate leukemia cells expressing CD19215,216. Additionally, investigating the role RAG-induced genomic instability in cancer development could lead to new diagnostic and prognostic advances. For instance, expression patterns of specific microRNAs hold promise for non-invasive early detection. In chronic lymphocytic leukemia (CLL), low expression of miR-34a was associated with shorter overall survival and worse responses to fludarabine, cyclophosphamide, rituximab (FCR) therapy. MiR-34a is induced in response to DDR activation and p53 stabilisation and was shown to limit the BCR signaling in CLL during DDR by down-modulating FOXP1217. Overexpression of miR-196b has been associated with poor prognosis and chemotherapy resistance in B cell ALL. It regulates the expression of HOXA9, a transcription factor involved in hematopoietic development, and contributes to leukemogenesis by promoting cell proliferation and inhibiting apoptosis218.
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