Journal Article

p15<sup>INK4b</sup> plays a crucial role in murine lymphoid development and tumorigenesis

Kwame Osei-Sarfo, Ignacio Perez de Castro and Angel Pellicer

in Carcinogenesis

Volume 33, issue 3, pages 708-713
Published in print March 2012 | ISSN: 0143-3334
Published online January 2012 | e-ISSN: 1460-2180 | DOI:
p15INK4b plays a crucial role in murine lymphoid development and tumorigenesis

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To investigate if the cooperation between the Rgr oncogene and the inactivation of INK4b (a CDK inhibitor), as described previously in a sarcoma model, would be operational in a lymphoid system in vivo, we generated a transgenic/knockout murine model. Transgenic mice expressing the Rgr oncogene under a CD4 promoter were crossed into a p15INK4b-deficient background. Unexpectedly, mice with a complete ablation of both p15INK4b alleles had a lower tumor incidence and higher survival rate when compared with CD4-Rgr progeny with homozygous or heterozygous expression of p15INK4b. Also, a similar survival pattern was observed in a parallel model in which transgenic mice expressing a constitutively activated N-Ras mutant were crossed into a p15INK4b-deficient background. To analyze this paradoxical event, we investigated the hypothesis that the absence of both p15INK4b alleles in the presence of the Rgr oncogene could be deleterious for proper thymocyte development. When analyzed, thymocyte development was blocked at the double negative (DN) 3 and DN4 stages in mice missing one or both alleles of p15INK4b, respectively. We found reduction in overall apoptotic levels in the thymocytes of mice expressing Rgr, compared with their wild-type mice, supporting thymocyte escape from programmed cell death and subsequently facilitating the onset of thymic lymphomas but less for those missing both p15 alleles. These findings provide evidence of the complex interplay between oncogenes and tumor suppressor genes in tumor development and indicate that in the lymphoid tissue the inactivation of both p15 alleles is unlikely to be the first event in tumor development.

Journal Article.  4892 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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