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Heterozygosity for Hypoxia Inducible Factor 1 Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model

¹ Abramson Family Cancer Research Institute, ² School of Veterinary Medicine, ³ School of Medicine, ⁴ Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: M. Celeste Simon, Howard Hughes Medical Institute, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, BRB II/III, Room 456, 421 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-746-5532; Fax: 215-746-5511; E-mail: celeste2{at}mail.med.upenn.edu.

Key Words: HIF1 • HIF2 • p53 • Notch • thymic lymphoma

Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and are overexpressed in a number of tumors. Although HIF1 and HIF2 share a high degree of sequence homology, recent work has shown that the two subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIF subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2 expression and Hif1^+/– mice to homozygotes for the R270H mutation in p53. Here, we report that p53^R270H/R270H mice, which have not been previously described, develop a unique tumor spectrum relative to p53^R270H/– mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1 significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1 levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. These observations uncover a novel role for HIF1 in Notch pathway activation during T-cell lymphomagenesis. [Cancer Res 2009;69(7):3213–20]