Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis

Jong Jin Jeong, Xiaorong Gu, Ji Nie, Sriram Sundaravel, Hui Liu, Wen Liang Kuo, Tushar D. Bhagat, Kith Pradhan, John Cao, Sangeeta Nischal, Kathy L. McGraw, Sanchari Bhattacharyya, Michael R. Bishop, Andrew Artz, Michael J. Thirman, Alison Moliterno, Peng Ji, Ross L. Levine, Lucy A. Godley, Ulrich G. SteidlJames J. Bieker, Alan F. List, Yogen Saunthararajah, Chuan He, Amit K. Verma, Amittha Wickrema

Research output: Contribution to journalArticle

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Abstract

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. SIGNIFICANCE: 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.This article is highlighted in the In This Issue feature, p. 681.

Original languageEnglish (US)
Pages (from-to)778-795
Number of pages18
JournalCancer discovery
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2019

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Cytosine
Hematopoiesis
Epigenomics
Phosphorylation
Cytokines
Myeloproliferative Disorders
Erythroid Cells
Mutation
Cytokine Receptors
Chromatin Assembly and Disassembly
Myelodysplastic Syndromes
Erythropoietin
Methylation
Tyrosine
Transcription Factors
Stem Cells
Genome
DNA
Enzymes
5-hydroxymethylcytosine

ASJC Scopus subject areas

  • Oncology

Cite this

Jeong, J. J., Gu, X., Nie, J., Sundaravel, S., Liu, H., Kuo, W. L., ... Wickrema, A. (2019). Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis. Cancer discovery, 9(6), 778-795. https://doi.org/10.1158/2159-8290.CD-18-1138

Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis. / Jeong, Jong Jin; Gu, Xiaorong; Nie, Ji; Sundaravel, Sriram; Liu, Hui; Kuo, Wen Liang; Bhagat, Tushar D.; Pradhan, Kith; Cao, John; Nischal, Sangeeta; McGraw, Kathy L.; Bhattacharyya, Sanchari; Bishop, Michael R.; Artz, Andrew; Thirman, Michael J.; Moliterno, Alison; Ji, Peng; Levine, Ross L.; Godley, Lucy A.; Steidl, Ulrich G.; Bieker, James J.; List, Alan F.; Saunthararajah, Yogen; He, Chuan; Verma, Amit K.; Wickrema, Amittha.

In: Cancer discovery, Vol. 9, No. 6, 01.06.2019, p. 778-795.

Research output: Contribution to journalArticle

Jeong, JJ, Gu, X, Nie, J, Sundaravel, S, Liu, H, Kuo, WL, Bhagat, TD, Pradhan, K, Cao, J, Nischal, S, McGraw, KL, Bhattacharyya, S, Bishop, MR, Artz, A, Thirman, MJ, Moliterno, A, Ji, P, Levine, RL, Godley, LA, Steidl, UG, Bieker, JJ, List, AF, Saunthararajah, Y, He, C, Verma, AK & Wickrema, A 2019, 'Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis', Cancer discovery, vol. 9, no. 6, pp. 778-795. https://doi.org/10.1158/2159-8290.CD-18-1138
Jeong, Jong Jin ; Gu, Xiaorong ; Nie, Ji ; Sundaravel, Sriram ; Liu, Hui ; Kuo, Wen Liang ; Bhagat, Tushar D. ; Pradhan, Kith ; Cao, John ; Nischal, Sangeeta ; McGraw, Kathy L. ; Bhattacharyya, Sanchari ; Bishop, Michael R. ; Artz, Andrew ; Thirman, Michael J. ; Moliterno, Alison ; Ji, Peng ; Levine, Ross L. ; Godley, Lucy A. ; Steidl, Ulrich G. ; Bieker, James J. ; List, Alan F. ; Saunthararajah, Yogen ; He, Chuan ; Verma, Amit K. ; Wickrema, Amittha. / Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis. In: Cancer discovery. 2019 ; Vol. 9, No. 6. pp. 778-795.
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abstract = "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. SIGNIFICANCE: 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.This article is highlighted in the In This Issue feature, p. 681.",
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T1 - Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis

AU - Jeong, Jong Jin

AU - Gu, Xiaorong

AU - Nie, Ji

AU - Sundaravel, Sriram

AU - Liu, Hui

AU - Kuo, Wen Liang

AU - Bhagat, Tushar D.

AU - Pradhan, Kith

AU - Cao, John

AU - Nischal, Sangeeta

AU - McGraw, Kathy L.

AU - Bhattacharyya, Sanchari

AU - Bishop, Michael R.

AU - Artz, Andrew

AU - Thirman, Michael J.

AU - Moliterno, Alison

AU - Ji, Peng

AU - Levine, Ross L.

AU - Godley, Lucy A.

AU - Steidl, Ulrich G.

AU - Bieker, James J.

AU - List, Alan F.

AU - Saunthararajah, Yogen

AU - He, Chuan

AU - Verma, Amit K.

AU - Wickrema, Amittha

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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. SIGNIFICANCE: 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.This article is highlighted in the In This Issue feature, p. 681.

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