Reduced Myc overexpression and normal B-cell differentiation mediate resistance to avian leukosis virus lymphomagenesis.
Avian leukosis virus (ALV) induces bursal lymphoma in tumor-susceptible chicken strains after proviral integration within the c-myc gene, and subsequent expansion of Myc-overexpressing lymphocytes within transformed follicles. Line 6(3) strain chickens are resistant to ALV tumorigenesis, largely failing to develop Myc-transformed follicles, although they show similar levels of ALV infection and integration as lymphoma-susceptible strains. Immunohistochemical analysis determined that the transformed follicles that do arise in lymphoma-resistant birds show much lower and more variable Myc overexpression than those of susceptible birds. This reduced Myc overexpression fails to block B-cell differentiation in resistant birds, while high Myc consistently blocks development at a late embryo stage in susceptible birds. This failure of Myc to block differentiation results in a normal pattern of posthatching bursal emigration in resistant transformed follicles, while transformed follicles of susceptible birds grow rapidly due to blocked emigration. Forced Myc overexpression produces transformed follicles in resistant birds, indicating that resistant lymphocytes can tolerate high Myc expression. The coding sequence and expression of the endogenous c-myc gene is the same in resistant and susceptible birds, suggesting that genetic resistance is instead mediated by reduced ALV LTR enhancer-driven transcription in the target lymphocytes of resistant birds.
Parghi
Sean S
SS
Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, PO Box 19024, MS C2-023, Seattle, WA 98109, USA.
Brandvold
Kimberly A
KA
Bowers
Sandra J
SJ
Neiman
Paul E
PE
Ruddell
Alanna
A
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D001353:Avian Leukosis / Q000235:genetics*; D001354:Avian Leukosis Virus / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology*; D002060:Bursa of Fabricius / Q000473:pathology; D002454:Cell Differentiation; D002472:Cell Transformation, Viral; D002642:Chick Embryo; D002645:Chickens; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011533:Proviruses / Q000235:genetics; D020079:Terminal Repeat Sequences; D016662:Virus Integration
D000944:Antigens, Differentiation, B-Lymphocyte; D016271:Proto-Oncogene Proteins c-myc