Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML

Hypoxia-inducible factor (HIF)-1 alpha accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2 alpha in hematopoietic cells is less clear. We investigated the role of HIF-2 alpha in leukemia and lymphoma cells. HIF-2 alpha expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2 alpha, we transduced human HIF-2 alpha cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2 alpha accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2 alpha died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2 alpha knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2 alpha mRNA was significantly elevated in several subsets such as the t(15; 17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2 alpha expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2 alpha overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.