title: Loss of HIF-1α accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia.
abstract: Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1α (HIF-1α) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1α loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1α leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1α loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1α deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1α. Some of our findings are in contrary to what has been previously described for the role of HIF-1α in other myeloid hematologic malignancies and question the potential of HIF-1α as a therapeutic target.
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Velasco-Hernandez
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Skanes University Hospital, Lund, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Tornero
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.|Department of Hematology, Skanes University Hospital, Lund, Sweden.|Department of Hematology, Linköping University Hospital, Linköping, Sweden.|Institution for Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Cammenga
mesh_terms: D000818:Animals; D002453:Cell Cycle; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3