PMID- 31728053
OWN - NLM
STAT- MEDLINE
DCOM- 20200901
LR  - 20240210
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 34
IP  - 4
DP  - 2020 Apr
TI  - Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in 
      JAK2V617F-positive myeloproliferative neoplasms.
PG  - 1062-1074
LID - 10.1038/s41375-019-0629-z [doi]
AB  - 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-1alpha 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.
FAU - Baumeister, Julian
AU  - Baumeister J
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Chatain, Nicolas
AU  - Chatain N
AUID- ORCID: 0000-0003-4485-3120
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Hubrich, Annika
AU  - Hubrich A
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Maie, Tiago
AU  - Maie T
AD  - Joint Research Center for Computational Biomedicine, RWTH Aachen University, 
      Aachen, Germany.
FAU - Costa, Ivan G
AU  - Costa IG
AUID- ORCID: 0000-0003-2890-8697
AD  - Joint Research Center for Computational Biomedicine, RWTH Aachen University, 
      Aachen, Germany.
FAU - Denecke, Bernd
AU  - Denecke B
AD  - Interdisciplinary Center for Clinical Research Aachen, Faculty of Medicine, RWTH 
      Aachen University, Aachen, Germany.
FAU - Han, Lijuan
AU  - Han L
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Kustermann, Caroline
AU  - Kustermann C
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
AD  - Institute of Biomedical Engineering, Department of Cell Biology, RWTH Aachen 
      University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical 
      Engineering, RWTH Aachen University, Aachen, Germany.
FAU - Sontag, Stephanie
AU  - Sontag S
AD  - Institute of Biomedical Engineering, Department of Cell Biology, RWTH Aachen 
      University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical 
      Engineering, RWTH Aachen University, Aachen, Germany.
FAU - Sere, Kristin
AU  - Sere K
AD  - Institute of Biomedical Engineering, Department of Cell Biology, RWTH Aachen 
      University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical 
      Engineering, RWTH Aachen University, Aachen, Germany.
FAU - Strathmann, Klaus
AU  - Strathmann K
AD  - Institute for Transfusion Medicine, RWTH Aachen University Medical School, 
      Aachen, Germany.
FAU - Zenke, Martin
AU  - Zenke M
AD  - Institute of Biomedical Engineering, Department of Cell Biology, RWTH Aachen 
      University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical 
      Engineering, RWTH Aachen University, Aachen, Germany.
FAU - Schuppert, Andreas
AU  - Schuppert A
AD  - Joint Research Center for Computational Biomedicine, RWTH Aachen University, 
      Aachen, Germany.
FAU - Brummendorf, Tim H
AU  - Brummendorf TH
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Kranc, Kamil R
AU  - Kranc KR
AD  - Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for 
      Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, 
      Charterhouse Square, London, UK.
FAU - Koschmieder, Steffen
AU  - Koschmieder S
AUID- ORCID: 0000-0002-1011-8171
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Gezer, Deniz
AU  - Gezer D
AD  - Department of Hematology, Oncology, Hemostaseology, and Stem Cell 
      Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. 
      dgezer@ukaachen.de.
LA  - eng
GR  - 14633/CRUK_/Cancer Research UK/United Kingdom
GR  - 26787/CRUK_/Cancer Research UK/United Kingdom
GR  - MR/P010008/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/P010008/2/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191114
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 512-64-1 (Echinomycin)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Apoptosis
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Cell Cycle
MH  - Cell Proliferation
MH  - Echinomycin/*pharmacology
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Induced Pluripotent Stem Cells/drug effects/metabolism/*pathology
MH  - Janus Kinase 2/*genetics
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Myeloproliferative Disorders/drug therapy/genetics/metabolism/*pathology
MH  - Prognosis
MH  - Tumor Cells, Cultured
EDAT- 2019/11/16 06:00
MHDA- 2020/09/02 06:00
CRDT- 2019/11/16 06:00
PHST- 2019/06/17 00:00 [received]
PHST- 2019/11/03 00:00 [accepted]
PHST- 2019/10/17 00:00 [revised]
PHST- 2019/11/16 06:00 [pubmed]
PHST- 2020/09/02 06:00 [medline]
PHST- 2019/11/16 06:00 [entrez]
AID - 10.1038/s41375-019-0629-z [pii]
AID - 10.1038/s41375-019-0629-z [doi]
PST - ppublish
SO  - Leukemia. 2020 Apr;34(4):1062-1074. doi: 10.1038/s41375-019-0629-z. Epub 2019 Nov 
      14.