4:LYMPHOMA SUPPRESSION:DNA BREAK REPAIR IN STEM CELLS AND THEIR MICROENVIRONMENT

Mainehealth, Portland ME

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The controlled induction of DNA strand breaks is critical for many cellular and developmental processes, but also poses the risk of genomic instability and consequent disease. The objectives of this project are to understand the roles of DNA double strand break repair in normal development within the hematopoietic system, and to assess whether specific cell types in the bone marrow hematopoietic niche may relate to cancer. DNA double strand break repair (DSBR) is increasingly recognized as a critical factor in preventing oncogenic chromosome instability in developing lymphocytes. Beyond this, roles have been suggested for DSBR in maintaining normal stem cell function and fitness over time. I hypothesize that DSBR is critical in both hematopoietic cells and their surrounding microenvironments to promote normal development and prevent neoplastic transformation. Using mice deficient for DSBR, with or without the tumor suppressor p53, we will test this hypothesis by 1) measuring the fitness and function of normal hematopoietic stem, progenitor, and progeny cells;and 2) evaluating tumorigenicity in DSBR competent or defective bone marrow and lymphoid microenvironments. Aim 1. To evaluate the extent to which NHEJ is required for normal function or homeostasis of cells in the hematopoietic compartment, we will: (1) measure HSC-derived cell populations in bone marrow and in the circulation, and test whether NHEJ-deficient HSCs or their proximate descendants are impaired for differentiation or function and (2) assess genome instability in NHEJ-deficient stem and progenitor cell populations Aim 2. To determine whether specific stem cell or lymphoid microenvironments participate in shaping the lymphoma phenotype, we will: (1) determine whether tumor latency, homing potential, or molecular etiology is differentially influenced by lympho-competent versus lympho-deficient bone marrow microenvironments;and (2) test whether tumor cells become adapted to specific secondary lymphoid microenvironments