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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的目的是评估DNA双链断裂修复在正常造血细胞和微环境中的作用，并评估骨髓微环境中的特定细胞类型是否与肿瘤发生有关。非同源末端连接(NHEJ)是一个关键的DSB修复途径，是发育中淋巴细胞中致癌基因组不稳定性的重要抑制因子。新的报告现在也指出了DSB修复在维持干细胞功能方面的作用，我们最近表明NHEJ是非淋巴组织中肿瘤发生的重要抑制因子。利用缺乏NHEJ因子Artemis和肿瘤抑制因子P53的小鼠，我们将检验我们的假设：1)NHEJ途径对于正常造血细胞的健康和功能至关重要，2)骨髓和淋巴微环境是前B细胞白血病和淋巴癌发生的关键决定因素。 目的1.为了评估NHEJ在多大程度上需要造血室细胞的正常功能或动态平衡，我们将： 1.1.测量骨髓和循环中的HSC来源的细胞群，并测试NHEJ缺陷的HSC是否在分化或适合性方面存在缺陷 1.2.评估NHEJ缺陷的干细胞和祖细胞群体的基因组不稳定性 目的2.为了确定特定的干细胞或淋巴微环境是否参与了淋巴瘤表型的形成，我们将： 2.1.确定肿瘤潜伏期、归巢潜能或分子病因学是否受淋巴功能和淋巴缺乏的骨髓微环境的不同影响 2.2.检测肿瘤细胞是否适应特定的次级淋巴微环境

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 objectives of this project are to evaluate the roles of DNA double strand break repair in normal hematopoietic cells and microenvironments, and to assess whether specific cell types in the bone marrow niche relate to tumorigenesis. Nonhomologous end joining (NHEJ), a critical DSB repair pathway, is an important suppressor of oncogenic genome instability in developing lymphocytes. New reports now also point to a role for DSB repair in maintaining stem cell function over time, and we have recently shown that NHEJ is an important suppressor of tumorigenesis in non-lymphoid tissues. Using mice deficient for the NHEJ factor ARTEMIS and for the tumor suppressor p53, we will test our hypotheses: 1) that the NHEJ pathway is critical for the fitness and function of normal hematopoietic cells, and 2) that bone marrow and lymphoid microenvironments are key determinants of pre-B cell leukemogenesis and lymphomagenesis. Aim 1. To evaluate the extent to which NHEJ is required for normal function or homeostasis of cells in the hematopoietic compartment, we will: 1.1. measure HSC-derived cell populations in bone marrow and in circulation, and test whether NHEJ-deficient HSCs show defects in differentiation or fitness 1.2. 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 lymphoma phenotype, we will: 2.1. determine whether tumor latency, homing potential, or molecular etiology is differentially influenced by lympho-competent versus lympho-deficient bone marrow microenvironments 2.2. test whether tumor cells become adapted to specific secondary lymphoid microenvironments