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 knock-in 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.

Hematologic toxicity in BRCA1 and BRCA2 mutation carriers during chemotherapy: A retrospective matched cohort study

“…There was no significant difference in BRCA status by regimen, time, or time squared interaction. Blood count patterns differed by chemotherapy regimen and within regimen by drug and dose intensity (Supporting Information [13][14]. Patterns in mutation carriers closely followed those in wild-type patients.…”

“…Reported toxicities included more frequent dose‐limiting neutropenia and neutropenic fever, cases of therapy‐related leukemia, and lower baseline blood counts. However, conclusions were limited by small sample size, lack of a comparable control population, and/or inability to evaluate those with BRCA1 vs BRCA2 mutations separately . Thus, we performed a multicenter, retrospective, matched cohort study to compare the frequency, severity, and timing of hematologic toxicities occurring throughout the multicycle curative intent chemotherapeutic regimens for breast cancer in women with and without an inherited BRCA1 or BRCA2 mutation.…”

53BP1 loss rescues embryonic lethality but not genomic instability of BRCA1 total knockout mice

“…This suggests that some mice die during late embryonic development, when hematopoietic organs are developed and hematopoietic stem cells transit from fetal liver to fetal bone marrow [40]. Recent studies have shown that BRCA1 is important for hematopoiesis [41,42]. Therefore, hematopoietic defects might account for the death of some Brca1 −/− ;Trp53bp1 −/− embryos during late embryonic development.…”

The DNA damage response pathway in normal hematopoiesis and malignancies

“…Notably, in the absence of a functional Fanconi anemia repair pathway, LT-HSCs show high rates of bone-marrow failure and cell death in response to stressinducing stimuli and markedly lower repopulating capacity compared to the wild-type cell counterparts [19]. Interestingly, Brca1 conditional deletion from embryonic hematopoietic cells determines pancytopenia and total loss of HSCs in the adult mice, while heterozygosity for a Brca1 mutant allele results in a modest yet significant decrease in white blood cells, as well as in a deficit in HSC self renewal potential, as assessed by serial bone-marrow transplantation [21], again emphasizing the role of DDR in HSC maintenance.…”