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Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.

Authors
  • Mgbemena, Victoria E1
  • Signer, Robert A J2
  • Wijayatunge, Ranjula1
  • Laxson, Travis1
  • Morrison, Sean J3
  • Ross, Theodora S4
  • 1 Department of Internal Medicine, Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Department of Pediatrics and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 Department of Pediatrics and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Internal Medicine, Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Jan 24, 2017
Volume
18
Issue
4
Pages
947–960
Identifiers
DOI: 10.1016/j.celrep.2016.12.075
PMID: 28122244
Source
Medline
Keywords
License
Unknown

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.

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