Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

Victoria E Mgbemena,Robert A.J Signer,Ranjula Wijayatunge,Travis Laxson,Sean J Morrison,Theodora S Ross

doi:10.1016/j.celrep.2016.12.075

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 requirementfor BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in theembryonic hematopoietic system (Vav1-iCre;Brca1F22-24/F22-24) developed hematopoietic defects in early adulthood that included reduced hematopoieticstem 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.

Highlights

Hematopoietic stem cells (HSCs) depend on DNA repair mechanisms to maintain their genomic integrity (Beerman et al, 2014; Mohrin et al, 2010; Rossi et al, 2007)
We evaluated the hematologic effects of chemotherapy on cancer patients with germline BRCA1 or BRCA2 mutations, and we found that, in our small cohort, BRCA1 mutations were associated with an increased risk of hematopoietic toxicity
Association of BRCA1 Mutations with Hematopoietic Toxicity from Chemotherapy Patients with germline BRCA1 mutations commonly develop cancers that are treated with DNA-damaging chemotherapies

Summary

Introduction

Hematopoietic stem cells (HSCs) depend on DNA repair mechanisms to maintain their genomic integrity (Beerman et al, 2014; Mohrin et al, 2010; Rossi et al, 2007). Fanconi anemia is caused by at least 18 different autosomal recessive mutants in the FA-BRCA repair pathway, including BRCA2 (Howlett et al, 2002; Xia et al, 2007), PALB2 (Reid et al, 2007), and BRIP1 (Seal et al, 2006). All three of these proteins physically interact with BRCA1 during DNA repair (Baer and Ludwig, 2002; Prakash et al, 2015; Xia et al, 2006; Zhang et al, 2009), raising the question of whether mutations in BRCA1 could influence HSC function or hematopoiesis. If loss-of-function mutations in BRCA1 impair DNA repair in hematopoietic cells, this would have broad implications for patients with BRCA1 mutations, as these patients are at increased risk of certain cancers that are commonly treated with DNA-damaging chemotherapies

Results

Discussion

Conclusion