Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis.
Tumorigenesis in rodents, as well as in humans, has been shown to be a multistep process, with each step reflecting an altered gene product or gene regulatory process leading to autonomy of cell growth. Initial genetic mutations are often associated with dysfunctional growth regulation, as is demonstrated in several transgenic mouse models. These changes are often followed by alterations in tumor suppressor gene function, allowing unchecked cell cycle progression and, by genomic instability, additional genetic mutations responsible for tumor metastasis. Here we show that reduced transforming growth factor-beta signaling in T lymphocytes leads to a rapid expansion of a CD8+ memory T-cell population and a subsequent transformation to leukemia/lymphoma as shown by multiple criteria, including peripheral blood cell counts histology, T-cell receptor monoclonality, and host transferability. Furthermore, spectral karyotype analysis of the tumors shows that the tumors have various chromosomal aberrations. These results suggest that reduced transforming growth factor-beta signaling acts as a primary carcinogenic event, allowing uncontrolled proliferation with consequent accumulation of genetic defects and leukemic transformation.
Lucas
Philip J
PJ
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
McNeil
Nicole
N
Hilgenfeld
Eva
E
Choudhury
Baishakhi
B
Kim
Seong-Jin
SJ
Eckhaus
Michael A
MA
Ried
Thomas
T
Gress
Ronald E
RE
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology; D002869:Chromosome Aberrations; D007156:Immunologic Memory; D015458:Leukemia, T-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II