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.
While 12% (1 in 8) of women will receive a breast cancer diagnosis in their lifetime, this rate jumps to as high as 87% for women who have a BRCA1 mutation. Gaps in our understanding of how and why breast cancer and other health issues develop in some women with BRCA1-mutant genomes but not in others negatively impacts our ability to treat and prevent these cancers. In the work proposed here, we will investigate hematopoietic abnormalities in BRCA1-mutant mice and humans to gain a better grasp on how BRCA1 mutations may contribute to excessive drug toxicities as well cancer development. As a greater percentage of cancer patients with BRCA1 mutations may experience compromised immune systems and infection following chemotherapy, understanding the role of BRCA1 in the hematopoietic response to these chemotherapy agents will ultimately improve our ability to prevent and treat cancer in these patients.
| Mersch, Jacqueline; Brown, Nichole; Pirzadeh-Miller, Sara et al. (2018) Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing. JAMA 320:1266-1274 |
| Mgbemena, Victoria E; Signer, Robert A J; Wijayatunge, Ranjula et al. (2017) Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function. Cell Rep 18:947-960 |
