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.
journal_name
Bloodjournal_title
Bloodauthors
Vasanthakumar A,Arnovitz S,Marquez R,Lepore J,Rafidi G,Asom A,Weatherly M,Davis EM,Neistadt B,Duszynski R,Vardiman JW,Le Beau MM,Godley LA,Churpek JEdoi
10.1182/blood-2015-03-635599subject
Has Abstractpub_date
2016-01-21 00:00:00pages
310-3issue
3eissn
0006-4971issn
1528-0020pii
blood-2015-03-635599journal_volume
127pub_type
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