Lymphocyte development is precisely controlled to enable generation of a diverse antigen receptor repertoire while, simultaneously, preventing deleterious events, such as translocations, which promote cellular transformation and lymphoid malignancies. These two dichotomous but interdependent processes are managed through the cooperation of diverse cellular signals, which control cell proliferation, survival, and antigen receptor assembly. We describe a novel signaling pathway in pre-B cells that is initiated by the physiologic DNA breaks generated during antigen receptor recombination. Surprisingly, our work demonstrates that DNA break-dependent signals paradoxically activate survival pathways that are important to ensure adequate time for antigen receptor gene rearrangement. However, if DNA breaks cannot be repaired, the same DNA damage responses trigger cell death to prevent translocations and protect genomic integrity. This temporal balance of survival and apoptosis is unique to physiologic DNA breaks as genotoxic insults, such as gamma irradiation, induce immediate cell death without an initial survival period. The goal of this project is to elucidate the mechanisms that coordinate survival and cell death signaling in response to DNA breaks in lymphocytes. Utilizing an experimental approach that permits isolation of DNA break signals and surface receptor signals, we propose to: 1) define the properties of physiologic DNA breaks that control survival kinetics, 2) identify the signals that regulate delayed apoptotic signaling in response to DNA breaks, and 3) define the functional integration of signals from DNA breaks and immune regulators (i.e., CD40) in the regulation of lymphocyte survival. Ultimately, this work will elucidate new signaling networks that balance survival and cell death in developing lymphocytes to ensure normal maturation and inhibit leukemogenesis. These investigations will establish the foundation for an independent scientific career focused on applying basic immunology research to the pathogenesis of clinical diseases, particularly immune deficiencies and lymphoid malignancies. The mentored period of this award will provide protect time to develop new techniques for studying DNA damage responses in lymphocytes and to acquire new skills necessary for managing a research laboratory. These tools will be essential for completion of the outlined experiments and for the germination of an independent research program. A collaborative and robust immunology research environment will help guide future research directions. This application presents a research program and a career development plan that will provide the framework and skills necessary for establishing independence and competing for extramural funding.
Developing immune cells intentionally generate breaks in their DNA to create a diverse immune response. This project investigates how immune cells respond to these DNA breaks to ensure correct repair and normal development while preventing errors that can lead to leukemias and lymphomas. Understanding these processes will provide new insights into the development and treatment of these malignancies.
|Steinel, Natalie C; Lee, Baeck-Seung; Tubbs, Anthony T et al. (2013) The ataxia telangiectasia mutated kinase controls Igýý allelic exclusion by inhibiting secondary Výý-to-Jýý rearrangements. J Exp Med 210:233-9|