title: Targeting HIF1α eliminates cancer stem cells in hematological malignancies.
abstract: 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, HIF1α signaling was selectively activated in the stem cells of mouse lymphoma and human acute myeloid leukemia (AML). HIF1a 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. Hif1α maintains mouse lymphoma CSCs by repressing a negative feedback loop in the Notch pathway. Taken together, our results demonstrate an essential function of Hif1α-Notch interaction in maintaining CSCs and provide an effective approach to target CSCs for therapy of hematological malignancies.
authors.affiliation: Division of Immunotherapy, Section of General Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D019337:Hematologic Neoplasms / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute; D008223:Lymphoma; D051379:Mice; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051880:Receptors, Notch