title: Hypoxia inducible factor-1α regulates a pro-invasive phenotype in acute monocytic leukemia.
abstract: Hypoxia inducible transcription factors (HIFs) are the main regulators of adaptive responses to hypoxia and are often activated in solid tumors, but their role in leukemia is less clear. In acute myeloid leukemia (AML), in particular, controversial new findings indicate that HIF-1α can act either as an oncogene or a tumor suppressor gene, and this may depend on the stage of leukemia development and/or the AML sub-type.In this study, we find that HIF-1α promotes leukemia progression in the acute monocytic leukemia sub-type of AML through activation of an invasive phenotype. By applying a list of validated HIF-1α-target genes to different AML sub-types, we identified a HIF-1α signature that typifies acute monocytic leukemia when compared with all other AML sub-types. We validated expression of this signature in cell lines and primary cells from AML patients. Interestingly, this signature is enriched for genes that control cell motility at different levels. As a consequence, inhibiting HIF-1α impaired leukemia cell migration, chemotaxis, invasion and transendothelial migration in vitro, and this resulted in impaired bone marrow homing and leukemia progression in vivo. Our data suggest that in acute monocytic leukemia an active HIF-1α-dependent pro-invasive pathway mediates the ability of leukemic cells to migrate and invade extramedullary sites and may be targeted to reduce leukemia dissemination.
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University School of Medicine, Milan, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Migliavacca
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Percio
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Valsecchi
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrero
authors.affiliation: Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Spinelli
authors.affiliation: Vita-Salute San Raffaele University School of Medicine, Milan, Italy.|Pathology Unit, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tresoldi
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Pattini
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Coltella
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007948:Leukemia, Monocytic, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D010641:Phenotype
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF-1α; acute monocytic leukemia; invasion; motility; self-renewal