Genomic instability in developing B-cells and B-cell leukemia Exploring the role of the RAG1/2 complex

This thesis investigates the pivotal role of the RAG1/2 complex in genomic instability during B-cell development and its implications for B-cell leukemia. The research highlights how aberrant targeting by RAG1/2 may lead to lymphoid malignancies, emphasizing the need to understand the regulation of RAG1/2 expression and activity in developing B cells.
The study reveals that RAG1/2 is responsible for inducing double-stranded DNA breaks not only at immunoglobulin loci but also at non-immunoglobulin sites, particularly near simple sequence repeats. This off-target activity raises concerns about the potential for genomic instability during B-cell maturation. Furthermore, the research identifies the DNA damage response as a crucial regulator of RAG1/2 expression, particularly through the ATM-FOXO1 signaling pathway, which responds to extrinsic DNA damage by downregulating RAG1/2 in pre-B cells.
Additionally, the thesis explores the roles of NF-κB and AKT signaling pathways in preventing inappropriate RAG1/2 expression and activity in transformed pre-B cells and B-cell acute lymphoblastic leukemia patients. Another significant finding is the identification of a feedback mechanism involving p53, which regulates RAG1 expression through microRNA-34a, further illustrating the complex interplay between DNA damage and RAG1/2 activity.
Overall, this research provides insights into the mechanisms that maintain genomic integrity during B-cell development and the potential consequences of RAG1/2 dysregulation, contributing to our understanding of the molecular underpinnings of B-cell malignancies.