Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms
Autor: | Tim H. Brümmendorf, Nicolas Chatain, Bernd Denecke, Caroline Küstermann, Klaus Strathmann, Tiago Maié, Stephanie Sontag, Martin Zenke, Annika Hubrich, Ivan G. Costa, Julian Baumeister, Andreas Schuppert, Steffen Koschmieder, Deniz Gezer, Kamil R. Kranc, Lijuan Han, Kristin Seré |
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Rok vydání: | 2019 |
Předmět: |
Adult
Male 0301 basic medicine Cancer Research Induced Pluripotent Stem Cells Apoptosis Echinomycin Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Polycythemia vera Biomarkers Tumor Tumor Cells Cultured medicine Humans Progenitor cell Myelofibrosis Aged Cell Proliferation Aged 80 and over Antibiotics Antineoplastic Myeloproliferative Disorders Essential thrombocythemia Cell Cycle Hematology Janus Kinase 2 Middle Aged Hypoxia-Inducible Factor 1 alpha Subunit Prognosis medicine.disease Warburg effect Gene Expression Regulation Neoplastic Haematopoiesis 030104 developmental biology medicine.anatomical_structure Oncology chemistry 030220 oncology & carcinogenesis Mutation Cancer research Female Bone marrow Follow-Up Studies |
Zdroj: | Leukemia. 34:1062-1074 |
ISSN: | 1476-5551 0887-6924 |
Popis: | Classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic malignancies including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2V617F mutation plays a central role in these disorders and can be found in 90% of PV and ~50-60% of ET and PMF. Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of the response to decreased oxygen levels. We demonstrate the impact of pharmacological inhibition and shRNA-mediated knockdown (KD) of HIF-1α in JAK2V617F-positive cells. Inhibition of HIF-1 binding to hypoxia response elements (HREs) with echinomycin, verified by ChIP, impaired growth and survival by inducing apoptosis and cell cycle arrest in Jak2V617F-positive 32D cells, but not Jak2WT controls. Echinomycin selectively abrogated clonogenic growth of JAK2V617F cells and decreased growth, survival, and colony formation of bone marrow and peripheral blood mononuclear cells and iPS cell-derived progenitor cells from JAK2V617F-positive patients, while cells from healthy donors were unaffected. We identified HIF-1 target genes involved in the Warburg effect as a possible underlying mechanism, with increased expression of Pdk1, Glut1, and others. That was underlined by transcriptome analysis of primary patient samples. Collectively, our data show that HIF-1 is a new potential therapeutic target in JAK2V617F-positive MPN. |
Databáze: | OpenAIRE |
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