RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice.
Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53(-/-) mice. Thus, potentially oncogenic DNA lesions are likely to also trigger apoptosis through additional, p53-independent processes. We found that loss of the BH3-only protein BIM accelerated lymphoma development in p53-deficient mice. This process was negated by concomitant loss of RAG1/2-mediated antigen receptor gene rearrangement. This demonstrates that BIM is critical for the induction of apoptosis caused by potentially oncogenic DNA lesions elicited by RAG1/2-induced gene rearrangement. Furthermore, this highlights the role of a BIM-mediated tumor suppressor pathway that acts in parallel to the p53 pathway and remains active even in the absence of wild-type p53 function, suggesting this may be exploited in the treatment of p53-deficient cancers.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia strasser@wehi.edu.au alex.delbridge@biogen.com.
Alex R D
0000-0001-7991-1760
AR
Delbridge
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Swee Heng Milon
0000-0001-7958-0244
SH
Pang
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Cassandra J
0000-0002-8891-8873
CJ
Vandenberg
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Stephanie
0000-0003-0467-7871
S
Grabow
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia Department of Clinical Haematology and Bone Marrow Transplant Service, the Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
Brandon J
0000-0002-1372-3107
BJ
Aubrey
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Lin
0000-0002-3881-8938
L
Tai
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Marco J
MJ
Herold
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia strasser@wehi.edu.au alex.delbridge@biogen.com.
Andreas
0000-0002-5020-4891
A
Strasser
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D063646:Carcinogenesis / Q000473:pathology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism*; D008223:Lymphoma / Q000473:pathology; D008810:Mice, Inbred C57BL; D045522:Recombinases / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000072224:Bcl-2-Like Protein 11; C435486:Bmf protein, mouse; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; D045522:Recombinases; D016159:Tumor Suppressor Protein p53; C064658:RAG-1 protein