Apoptosis-promoted tumorigenesis: γ-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death
- Ewa M. Michalak1,2,4,
- Cassandra J. Vandenberg1,
- Alex R.D. Delbridge1,2,
- Li Wu1,2,
- Clare L. Scott1,2,
- Jerry M. Adams1,2,3 and
- Andreas Strasser1,2,3,5
- 1The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3050, Australia;
- 2Department of Medical Biology, The University of Melbourne, Parkville VIC 3010, Australia
-
↵3 These authors contributed equally to this work.
Abstract
Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in γ-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from γ-irradiation-induced death, because their glucocorticoid-mediated decimation in Puma-deficient mice activated cycling of stem/progenitor cells and restored thymic lymphomagenesis. Our demonstration that cycles of cell attrition and repopulation by stem/progenitor cells can drive tumorigenesis has parallels in human cancers, such as therapy-induced malignancies.
Keywords
Footnotes
-
↵5 Corresponding author.
E-MAIL strasser{at}wehi.edu.au; FAX 61-3-9347-0852.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1940110.
-
Supplemental material is available at http://www.genesdev.org.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press