Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation.
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.
Labi
Verena
V
Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck 6020, Austria.
Erlacher
Miriam
M
Krumschnabel
Gerhard
G
Manzl
Claudia
C
Tzankov
Alexandar
A
Pinon
Josephina
J
Egle
Alexander
A
Villunger
Andreas
A
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
D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins