Heterozygosity For Hypoxia Inducible Factor 1 Alpha 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 arc over-expressed in a number of tumors. Although HIF1 alpha and HIF2 alpha share a high degree of sequence homology, recent work has shown that the two alpha subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIF alpha subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2 alpha expression and Hif1 alpha(+/-) 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(p270H/-) mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1 alpha significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1 alpha 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 alpha in Notch pathway activation during T-cell lymphomagenesis. [Cancer Res 2009;69(7):3213-20]