title: Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation.
abstract: Apoptosis triggered by p53 upon DNA damage secures removal of cells with compromised genomes, and is thought to prevent tumorigenesis. In contrast, we provide evidence that p53-induced apoptosis can actively drive tumor formation. Mice defective in p53-induced apoptosis due to loss of its proapoptotic target gene, puma, resist gamma-irradiation (IR)-induced lymphomagenesis. In wild-type animals, repeated irradiation injury-induced expansion of hematopoietic stem/progenitor cells (HSCs) leads to lymphoma formation. Puma(-/-) HSCs, protected from IR-induced cell death, show reduced compensatory proliferation and replication stress-associated DNA damage, and fail to form thymic lymphomas, demonstrating that the maintenance of stem/progenitor cell homeostasis is critical to prevent IR-induced tumorigenesis.
authors.affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck 6020, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Labi
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krumschnabel
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzl
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.forename: Josephina
authors.initials: J
authors.lastname: Pinon
authors.forename: Alexander
authors.initials: A
authors.lastname: Egle
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage / Q000528:radiation effects; D004261:DNA Replication; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000528:radiation effects; D007962:Leukocytes / Q000473:pathology* / Q000528:radiation effects; D008223:Lymphoma / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins