Targeting HIF1α Eliminates Cancer Stem Cells in Hematological Malignancies

Molecular targeting of cancer stem cells (CSCs) has therapeutic potential for efficient treatment of cancer, although relatively few specific targets have been identified so far. Hypoxia-inducible factor (HIF) was recently shown to regulate the tumorigenic capacity of glioma stem cells under hypoxic conditions. Surprisingly, we found that, under normoxia, HIF1 alpha signaling was selectively activated in the stem cells of mouse lymphoma and human acute myeloid leukemia (AML). HIF1 alpha shRNA and HIF inhibitors abrogated the colony-forming unit (cfu) activity of mouse lymphoma and human AML CSCs. Importantly, the HIF-inhibitor echinomycin efficiently eradicated mouse lymphoma and serially transplantable human AML in xenogeneic models by preferential elimination of CSCs. Hif1 alpha maintains mouse lymphoma CSCs by repressing a negative feedback loop in the Notch pathway. Taken together, our results demonstrate an essential function of Hif1 alpha-Notch interaction in maintaining CSCs and provide an effective approach to target CSCs for therapy of hematological malignancies.