The Roles and Regulation of BRCA1 in Hematopoiesis

项目总结 BRCA1在正常和肿瘤骨髓细胞中的作用 我们最近发现BRCA1是正常造血所必需的，但BRCA1的突变 造血细胞中的这种基因很少使携带者患上白血病。我们收集了一个 作为这里提出的研究的基础的收敛数据集的数量。 首先，我们发现BRCA1突变杂合子的人类可能有更高的 化疗相关的中性粒细胞减少症的风险。第二，BRCA1基因缺陷的小鼠 造血系统经历骨髓衰竭与严重造血相关 干细胞和祖细胞缺陷，第三，BRCA1缺乏杂合子小鼠有轻微的 功能有问题的造血干细胞导致的骨髓重建缺陷 活动。从这些数据中，我们提出了两个我们打算测试的假设：BRCA1 是正常造血所必需的，而BRCA1在紧急粒细胞生成中起作用， 这是造血祖细胞对感染或其他应激源的急性反应。我们 提出BRCA1受干扰素调节因子8(IRF8)表达的调节，即 由感染或其他导致紧急粒细胞生成的压力引起的。有趣的是，一个 BRCA1对造血的绝对需求可能解释了为什么BRCA1患者 突变不会增加患白血病的风险：它们的骨髓干细胞和祖细胞 没有BRCA1的细胞在这些细胞有机会转化之前就会死亡。在这里，我们将首先 确定BRCA1维持正常造血所需的细胞和分子事件 并使用人源化的BRCA1检测不同人类BRCA1突变的表型 老鼠模型。我们还将对更多来自我们癌症遗传学的患者进行研究 临床检测BRCA1突变与造血毒性的关系。最后， 我们将检查应激粒细胞生成过程中BRCA1水平的增加以及BRCA1 在这一途径中发挥作用。这一领域的调查尚未探索，我们的结果将有助于 更好地了解BRCA1在正常和肿瘤造血中的要求 化疗对患者的毒性，最终导致遗传性疾病治疗的改进 乳腺癌和卵巢癌综合征患者以及对组织特异性的洞察 BRCA1突变相关的肿瘤发生。

PROJECT SUMMARY Role of BRCA1 in normal and neoplastic bone marrow cells We have recently discovered that Brca1 is necessary for normal hematopoiesis, but mutation of this gene in hematopoietic cells rarely predispose carriers to leukemia. We have collected a number of convergent data sets that serve as the foundation for the studies proposed here. First, we have found that humans heterozygous for BRCA1 mutations may have an increased risk for chemotherapy-associated febrile neutropenia. Second, mice deficient for Brca1 in the hematopoietic system experience bone marrow failure associated with severe hematopoietic stem cell and progenitor defects, and third, mice heterozygous for Brca1 deficiency have slight defects in bone marrow reconstitution due to problematic functional hematopoietic stem cell activity. From these data, we have developed two hypotheses that we propose to test: BRCA1 is required for normal hematopoiesis and BRCA1 plays a role in emergency granulopoiesis, which is the acute response of hematopoietic progenitors to infection or other stressors. We propose that BRCA1 is regulated by interferon regulatory factor 8 (IRF8) expression, which is induced by infections or other stresses that lead to emergency granulopoiesis. Interestingly, an absolute requirement of BRCA1 for hematopoiesis may explain why people with BRCA1 mutations do not have an increased risk for leukemia: their bone marrow stem and progenitor cells die without BRCA1 before these cells have a chance to transform. Here, we will first identify the cellular and molecular events required for Brca1 to maintain normal hematopoiesis and examine the phenotypes of different human BRCA1 mutations using a humanized Brca1 mouse model. We will also conduct a study with additional patients from our cancer genetics clinic to examine the relationship between BRCA1 mutations and hematopoietic toxicity. Finally, we will examine the increases in BRCA1 levels during stress granulopoiesis and BRCA1 function in this pathway. This area of investigation is unexplored, and our results will facilitate a better understanding of the requirements for Brca1 in normal and neoplastic hematopoiesis and the chemotherapy toxicities in patients, ultimately leading to improved treatment of hereditary breast and ovarian cancer syndrome patients as well as insight into the tissue specificity of BRCA1 mutation-associated tumorigenesis.