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- Jong Jin Jeong
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Xiaorong Gu
- 2Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.
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- Ji Nie
- 3Department of Chemistry, The University of Chicago, Chicago, Illinois.
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- Sriram Sundaravel
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Hui Liu
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Wen-Liang Kuo
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Tushar D. Bhagat
- 4Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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- Kith Pradhan
- 4Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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- John Cao
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Sangeeta Nischal
- 4Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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- Kathy L. McGraw
- 5Moffitt Cancer Center, Tampa, Florida.
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- Sanchari Bhattacharyya
- 4Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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- Michael R. Bishop
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Andrew Artz
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Michael J. Thirman
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Alison Moliterno
- 6Department of Hematology, Johns Hopkins School of Medicine, Baltimore, Maryland.
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- Peng Ji
- 7Department of Pathology, Northwestern University, Chicago, Illinois.
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- Ross L. Levine
- 8Memorial Sloan Kettering Cancer Center, New York, New York.
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- Lucy A. Godley
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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- Ulrich Steidl
- 4Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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- James J. Bieker
- 9Department of Cell, Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York.
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- Alan F. List
- 5Moffitt Cancer Center, Tampa, Florida.
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- Yogen Saunthararajah
- 2Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.
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- Chuan He
- 3Department of Chemistry, The University of Chicago, Chicago, Illinois.
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- Amit Verma
- 4Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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- Amittha Wickrema
- 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor–associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. The activating JAK2V617F mutation seen in myeloproliferative disease patient samples and in mouse models is associated with increased TET activity and cytosine hydroxymethylation as well as genome-wide loss of cytosine methylation. These epigenetic and functional changes are also associated with increased expression of several oncogenic transcripts. Thus, we demonstrate that JAK2-mediated TET2 phosphorylation provides a mechanistic link between extracellular signals and epigenetic changes during hematopoiesis.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Identification of TET2 phosphorylation and activation by cytokine-stimulated JAK2 links extracellular signals to chromatin remodeling during hematopoietic differentiation. This provides potential avenues to regulate TET2 function in the context of myeloproliferative disorders and myelodysplastic syndromes associated with the JAK2V617F-activating mutation.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 681</jats:p> </jats:sec>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 9 (6), 778-795, 2019-06-01
American Association for Cancer Research (AACR)