Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

Summary BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system ( Vav1 - iCre ; Brca1 F22–24/F22–24 ) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a hu BRCA1 knockin allele ( Brca1 BRCA1/BRCA1 ) were normal, mice with a mutant hu BRCA1 /5382insC allele and a null allele ( Mx1 - Cre ; Brca1 F22–24/5382insC ) had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction.