V-myc in a simple, single gene retroviral vector causes rapid induction of leukemia and concomitant apoptosis following bone marrow transplantation.
We have previously developed an in vivo model of leukemogenesis utilizing mice reconstituted with genetically modified bone marrow cells. Based on those studies, a new single gene retroviral vector has been engineered which efficiently transfers v-myc into immature murine bone marrow cells. All reconstituted mice developed leukemia with a short latency period (5-11 weeks). In addition to hyperproliferation associated with elevated levels of PCNA, extensive apoptosis was also observed in all leukemic animals with p53 accumulating in the apoptotic cells. Whereas bax encoded protein, an effector of p53 apoptotic activity was detected in apoptotic cells, p21Waf1 protein, a potential mediator of p53 growth suppression was not detected in these cells suggesting that v-myc-induced apoptosis was independent of the ability of p53 to induce p21Waf1. These results indicate that apoptosis, a part of the cellular response to v-myc expression, does not prevent leukemia development and that hyperproliferation rather than abrogation of oncogene-induced apoptosis appears to be a critical event in v-myc-induced leukemia.
Dolnikov
A
A
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, Australia.
Shounan
Y
Y
Millington
M
M
Mackenzie
K
K
Symonds
G
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000502:physiology; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D005260:Female; D016259:Genes, myc / Q000502:physiology*; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D007942:Leukemia, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016662:Virus Integration
D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53