Data from Heterozygosity for <i>Hypoxia Inducible Factor 1α</i> Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model

Abstract

<div>Abstract<p>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 <i>Hif1α<sup>+/−</sup></i> mice to homozygotes for the R270H mutation in <i>p53</i>. Here, we report that <i>p53<sup>R270H/R270H</sup></i> mice, which have not been previously described, develop a unique tumor spectrum relative to <i>p53<sup>R270H/−</sup></i> mice, including a high incidence of thymic lymphomas. Heterozygosity for <i>Hif1α</i> significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced <i>Hif1α</i> levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, <i>Dtx1</i> and <i>Nrarp</i>. These observations uncover a novel role for HIF1α in Notch pathway activation during T-cell lymphomagenesis. [Cancer Res 2009;69(7):3213–20]</p></div>