Heterozygosity for Hypoxia Inducible Factor 1α decreases the incidence of thymic lymphomas in a p53 mutant mouse model

Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and are overexpressed in a number of tumors. Although HIF1α and HIF2α share a high degree of sequence homology, recent work has shown that the two α subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFα subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2α expression and Hif1α +/− 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 Hif1α significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1α 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 HIF1α in Notch pathway activation during T-cell lymphomagenesis. [Cancer Res 2009;69(7):3213–20]