Carcinogenesis, Vol. 20, No. 9, 1675-1682,
September 1999
© 1999 Oxford University Press
Cancer Biology |
Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas
1 Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA and
2 Laboratorio de Genética Molecular Humana, Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Alterations in the Rb pathway have been described in many different tumors. In order to study this cell cycle regulatory mechanism in murine T cell lymphomas, we have analyzed the RNA and protein expression of the cyclin D1, cdk4 and retinoblastoma genes in primary tumor samples. We have detected overexpression of the cyclin D1 gene and deficient expression of the retinoblastoma gene in 42 and 28% of these tumors, respectively. The immunohistochemical analysis showed that these RT–PCR results are correlated with a significant increase in the number of positive cells for cyclin D1 and a moderate decrease in the expression of Rb protein, respectively. The analysis of cyclin D1, Rb, p15INK4b and p16INK4a showed that 75% of lymphomas had alterations in these genes and indicates that the Rb pathway is frequently altered in mouse primary T cell lymphomas. Moreover, 31% of lymphomas presented simultaneous alterations in at least two of these genes, suggesting the importance of concurrent alteration of different Rb pathway regulators. In addition, we have characterized these samples for mutational status of the N-ras and K-ras genes. We have only detected mutations in codon 12 of K-ras in six of 49 lymphomas (12%). Interestingly, five of these lymphomas also showed alterations in at least one of the Rb pathway regulators analyzed here. Taken together, these data suggest that deregulation of the Rb pathway regulators and/or oncogenic activation of K-ras may represent a common important clue in progression of murine T cell lymphomas.
Abbreviations: DAB, diaminobenzidine; NMU, N-methyl-N-nitrosourea; TLSR1, thymic lymphoma suppressor region 1.
3 To whom correspondence should be addressed at: Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA Email: perezi01{at}popmail.med.nyu.edu..
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