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

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

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24 Scopus citations

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;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.

Original language	English (US)
Pages (from-to)	947-960
Number of pages	14
Journal	Cell Reports
Volume	18
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2016.12.075
State	Published - Jan 24 2017

Keywords

BRCA1 mutations
Cre
Fanconi anemia
gene targeting
hematopoiesis
hematopoietic stem cells
humanization
pancytopenia

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2016.12.075

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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.",

keywords = "BRCA1 mutations, Cre, Fanconi anemia, gene targeting, hematopoiesis, hematopoietic stem cells, humanization, pancytopenia",

author = "Mgbemena, {Victoria E.} and Signer, {Robert A J} and Ranjula Wijayatunge and Travis Laxson and Morrison, {Sean J.} and Ross, {Theodora S.}",

note = "Funding Information: We are grateful to Dr. Martin Dietrich, Lesli Kiedrowski, Abigail Soyombo, and other members of the T.S.R. lab for their technical assistance and intellectual contributions. This work was supported by National Cancer Institute grants to T.S.R. (R01 CA82363-03 and R01 CA098730-01), the Lucy and Henry Billingsley Fund, and a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (BWF 1007448.01; T.S.R.). V.E.M. was supported by the NIH (5T32 CA124334-09 and 2T32 CA124334-06) and the Cancer Prevention and Research Institute of Texas (CPRIT, RP140110). S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryne and Gene Bishop Distinguished Chair in Pediatric Genetics, the director of the Hamon Laboratory for Stem Cells and Cancer, and a CPRIT Scholar. T.S.R. holds the Jeanne Ann Plitt Professorship in Breast Cancer Research and the H. Ben and Isabelle T. Decherd Chair in Internal Medicine at UT Southwestern Medical Center. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

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AU - Mgbemena, Victoria E.

AU - Signer, Robert A J

AU - Wijayatunge, Ranjula

AU - Laxson, Travis

AU - Morrison, Sean J.

AU - Ross, Theodora S.

N1 - Funding Information: We are grateful to Dr. Martin Dietrich, Lesli Kiedrowski, Abigail Soyombo, and other members of the T.S.R. lab for their technical assistance and intellectual contributions. This work was supported by National Cancer Institute grants to T.S.R. (R01 CA82363-03 and R01 CA098730-01), the Lucy and Henry Billingsley Fund, and a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (BWF 1007448.01; T.S.R.). V.E.M. was supported by the NIH (5T32 CA124334-09 and 2T32 CA124334-06) and the Cancer Prevention and Research Institute of Texas (CPRIT, RP140110). S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryne and Gene Bishop Distinguished Chair in Pediatric Genetics, the director of the Hamon Laboratory for Stem Cells and Cancer, and a CPRIT Scholar. T.S.R. holds the Jeanne Ann Plitt Professorship in Breast Cancer Research and the H. Ben and Isabelle T. Decherd Chair in Internal Medicine at UT Southwestern Medical Center. Publisher Copyright: © 2017 The Author(s)

PY - 2017/1/24

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N2 - 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.

AB - 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.

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KW - Fanconi anemia

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KW - humanization

KW - pancytopenia

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Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

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