Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

Victoria E. Mgbemena, Robert A J Signer, Ranjula Wijayatunge, Travis Laxson, Sean J. Morrison, Theodora S. Ross

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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;Brca1F22–24/F22–24) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1BRCA1/BRCA1) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1F22–24/5382insC) 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.

Original languageEnglish (US)
Pages (from-to)947-960
Number of pages14
JournalCell Reports
Volume18
Issue number4
DOIs
StatePublished - Jan 24 2017

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Keywords

  • BRCA1 mutations
  • Cre
  • Fanconi anemia
  • gene targeting
  • hematopoiesis
  • hematopoietic stem cells
  • humanization
  • pancytopenia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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