title: Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.
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.
authors.affiliation: Department of Internal Medicine, Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Mgbemena
authors.affiliation: 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.
authors.forename: Robert A J
authors.initials: RAJ
authors.lastname: Signer
authors.affiliation: Department of Internal Medicine, Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ranjula
authors.initials: R
authors.lastname: Wijayatunge
authors.affiliation: Department of Internal Medicine, Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Laxson
authors.affiliation: 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.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
authors.affiliation: Department of Internal Medicine, Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: theo.ross@utsouthwestern.edu.
authors.forename: Theodora S
authors.initials: TS
authors.lastname: Ross
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001772:Blood Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D016296:Mutagenesis; D010198:Pancytopenia / Q000209:etiology / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D006454:Hemoglobins; D003520:Cyclophosphamide
keywords: BRCA1 mutations; Cre; Fanconi anemia; gene targeting; hematopoiesis; hematopoietic stem cells; humanization; pancytopenia