Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death.
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 gamma-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 gamma-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.
Michalak
Ewa M
EM
The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3050, Australia.
Vandenberg
Cassandra J
CJ
Delbridge
Alex R D
AR
Wu
Li
L
Scott
Clare L
CL
Adams
Jerry M
JM
Strasser
Andreas
A
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008223:Lymphoma / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013953:Thymus Neoplasms / Q000235:genetics / Q000503:physiopathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone