Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation
- Verena Labi1,
- Miriam Erlacher1,2,
- Gerhard Krumschnabel1,
- Claudia Manzl1,
- Alexandar Tzankov3,
- Josephina Pinon4,
- Alexander Egle4 and
- Andreas Villunger1,5
- 1Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck 6020, Austria;
- 2Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Freiburg, Freiburg 79106, Germany;
- 3Institute for Pathology, University of Basel, Basel 4031, Switzerland;
- 4Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Paracelsus Medical University, Salzburg 5020, Austria
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 γ-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.
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Footnotes
↵5 Corresponding author.
E-MAIL andreas.villunger{at}i-med.ac.at; FAX 43-512-507-2867.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1940210.
Supplemental material is available at http://www.genesdev.org.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
