Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

Publication date: 24 January 2017
Source:Cell Reports, Volume 18, Issue 4
Author(s): Victoria E. Mgbemena, Robert A.J. Signer, Ranjula Wijayatunge, Travis Laxson, Sean J. Morrison, Theodora S. Ross
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;Brca1^{F22–24/F22–24}) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1^BRCA1/BRCA1) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1^{F22–24/5382insC}) 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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Teaser

Mgbemena et al. report that hematopoietic stem cells have an absolute requirement for Brca1 to survive. They also show that humanization of the mouse Brca1 gene with a knocked-in human BRCA1 cDNA, but not a mutant BRCA1/5382insC cDNA, fully substitutes for mouse Brca1 during both embryonic development and hematopoiesis.


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