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Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms.
- Source :
-
Leukemia [Leukemia] 2020 Apr; Vol. 34 (4), pp. 1062-1074. Date of Electronic Publication: 2019 Nov 14. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Antibiotics, Antineoplastic pharmacology
Apoptosis
Biomarkers, Tumor genetics
Cell Cycle
Cell Proliferation
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Induced Pluripotent Stem Cells drug effects
Induced Pluripotent Stem Cells metabolism
Male
Middle Aged
Myeloproliferative Disorders drug therapy
Myeloproliferative Disorders genetics
Myeloproliferative Disorders metabolism
Prognosis
Tumor Cells, Cultured
Biomarkers, Tumor metabolism
Echinomycin pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Induced Pluripotent Stem Cells pathology
Janus Kinase 2 genetics
Mutation
Myeloproliferative Disorders pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 34
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 31728053
- Full Text :
- https://doi.org/10.1038/s41375-019-0629-z