Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice

Blood. 2016 Jan 21;127(3):310-3. doi: 10.1182/blood-2015-03-635599. Epub 2015 Dec 7.

Abstract

BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion. Mice lacking Brca1 in the BM have baseline cytopenias and develop spontaneous bone marrow failure or diverse hematologic malignancies by 6 months of age. Brca1(-/-) BM cells have a reduced capacity to form hematopoietic colonies in vitro and to reconstitute hematopoiesis in irradiated recipients, consistent with a hematopoietic progenitor functional defect. Brca1(-/-) BM cells also show FA-like hypersensitivity to the DNA crosslinking agent mitomycin C, and karyotypes feature genomic instability. Taken together, our results show that loss of Brca1 in murine BM causes hematopoietic defects similar to those seen in people with FA, which provides strong evidence that Brca1 is critical for normal hematopoiesis and that Brca1 is a bona fide FA-like gene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Aplastic
  • Animals
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / genetics*
  • Bone Marrow / pathology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Bone Marrow Diseases
  • Bone Marrow Failure Disorders
  • Disease Models, Animal
  • Genomic Instability
  • Hematologic Neoplasms / diagnosis
  • Hematologic Neoplasms / genetics*
  • Hematopoiesis / genetics
  • Hemoglobinuria, Paroxysmal / diagnosis
  • Hemoglobinuria, Paroxysmal / genetics*
  • Humans
  • Leukemic Infiltration
  • Leukocyte Count
  • Mice
  • Mice, Knockout
  • Pancytopenia / genetics
  • Pancytopenia / pathology
  • Phenotype

Substances

  • BRCA1 Protein

Supplementary concepts

  • Bone Marrow failure syndromes