title: Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice.
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.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Aparna
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Rafael
authors.initials: R
authors.lastname: Marquez
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Janet
authors.initials: J
authors.lastname: Lepore
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: George
authors.initials: G
authors.lastname: Rafidi
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Anase
authors.initials: A
authors.lastname: Asom
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Madison
authors.initials: M
authors.lastname: Weatherly
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Barbara
authors.initials: B
authors.lastname: Neistadt
authors.affiliation: Section of Hematology/Oncology, Department of Medicine.
authors.forename: Robert
authors.initials: R
authors.lastname: Duszynski
authors.affiliation: Department of Pathology.
authors.forename: James W
authors.initials: JW
authors.lastname: Vardiman
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine Comprehensive Cancer Center, and.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine Comprehensive Cancer Center, and Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine Comprehensive Cancer Center, and Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Churpek
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics*; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D004195:Disease Models, Animal; D042822:Genomic Instability; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006457:Hemoglobinuria, Paroxysmal / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D017254:Leukemic Infiltration; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D010198:Pancytopenia / Q000235:genetics / Q000473:pathology; D010641:Phenotype
chemical_list: D019313:BRCA1 Protein