title: Caspase-9 is required for normal hematopoietic development and protection from alkylator-induced DNA damage in mice.
abstract: Apoptosis and the DNA damage responses have been implicated in hematopoietic development and differentiation, as well as in the pathogenesis of myelodysplastic syndromes (MDS) and leukemia. However, the importance of late-stage mediators of apoptosis in hematopoiesis and leukemogenesis has not been elucidated. Here, we examine the role of caspase-9 (Casp9), the initiator caspase of the intrinsic apoptotic cascade, in murine fetal and adult hematopoiesis. Casp9 deficiency resulted in decreased erythroid and B-cell progenitor abundance and impaired function of hematopoietic stem cells after transplantation. Mouse bone marrow chimeras lacking Casp9 or its cofactor Apaf1 developed low white blood cell counts, decreased B-cell numbers, anemia, and reduced survival. Defects in apoptosis have also been previously implicated in susceptibility to therapy-related leukemia, a disease caused by exposure to DNA-damaging chemotherapy. We found that the burden of DNA damage was increased in Casp9-deficient cells after exposure to the alkylator, N-ethyl-nitrosourea (ENU). Furthermore, exome sequencing revealed that oligoclonal hematopoiesis emerged in Casp9-deficient bone marrow chimeras after alkylator exposure. Taken together, these findings suggest that defects in apoptosis could be a key step in the pathogenesis of alkylator-associated secondary malignancies.
authors.affiliation: Department of Medicine, Division of Oncology.
authors.forename: Elise Peterson
authors.initials: EP
authors.lastname: Lu
authors.affiliation: The Genome Institute.
authors.forename: Michael
authors.initials: M
authors.lastname: McLellan
authors.affiliation: Department of Medicine, Division of Oncology, The Genome Institute, Siteman Cancer Center, and.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: The Genome Institute.
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.affiliation: The Genome Institute, Siteman Cancer Center, and Department of Genetics, Washington University, St. Louis, MO.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: The Genome Institute, Siteman Cancer Center, and Department of Genetics, Washington University, St. Louis, MO.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: The Genome Institute.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Oncology, Siteman Cancer Center, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Department of Medicine, Division of Oncology, Siteman Cancer Center, and.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Department of Medicine, Division of Oncology, Siteman Cancer Center, and.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: Department of Medicine, Division of Oncology, Siteman Cancer Center, and Department of Genetics, Washington University, St. Louis, MO.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: Department of Medicine, Division of Oncology, The Genome Institute, Siteman Cancer Center, and Department of Genetics, Washington University, St. Louis, MO.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: Department of Medicine, Division of Oncology, Siteman Cancer Center, and.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology; D053453:Caspase 9 / Q000502:physiology*; D003433:Crosses, Genetic; D004249:DNA Damage; D005038:Ethylnitrosourea / Q000737:chemistry; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000378:metabolism; D010641:Phenotype
chemical_list: D000477:Alkylating Agents; C506434:Casp9 protein, mouse; D053453:Caspase 9; D005038:Ethylnitrosourea