Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib

Mutations of calreticulin ( CALR ) are detected in 25–30% of patients with essential thrombocythemia (ET) or primary myelofibrosis and cause frameshifts that result in proteins with a novel C-terminal. We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (S...

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Veröffentlicht in:Leukemia 2017-05, Vol.31 (5), p.1136-1144
Hauptverfasser: Shide, K, Kameda, T, Yamaji, T, Sekine, M, Inada, N, Kamiunten, A, Akizuki, K, Nakamura, K, Hidaka, T, Kubuki, Y, Shimoda, H, Kitanaka, A, Honda, A, Sawaguchi, A, Abe, H, Miike, T, Iwakiri, H, Tahara, Y, Sueta, M, Hasuike, S, Yamamoto, S, Nagata, K, Shimoda, K
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container_end_page 1144
container_issue 5
container_start_page 1136
container_title Leukemia
container_volume 31
creator Shide, K
Kameda, T
Yamaji, T
Sekine, M
Inada, N
Kamiunten, A
Akizuki, K
Nakamura, K
Hidaka, T
Kubuki, Y
Shimoda, H
Kitanaka, A
Honda, A
Sawaguchi, A
Abe, H
Miike, T
Iwakiri, H
Tahara, Y
Sueta, M
Hasuike, S
Yamamoto, S
Nagata, K
Shimoda, K
description Mutations of calreticulin ( CALR ) are detected in 25–30% of patients with essential thrombocythemia (ET) or primary myelofibrosis and cause frameshifts that result in proteins with a novel C-terminal. We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic CMK11-5 cells and erythroleukemic F-36P-MPL cells with knocked-in CALR mutations showed increased growth and acquisition of cytokine-independent growth, respectively, accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation with a 52 bp deletion ( CALR del52-transgenic mice (TG)) developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow (BM) mature megakaryocytes. CALR del52 BM cells did not drive away wild-type (WT) BM cells in in vivo competitive serial transplantation assays, suggesting that the self-renewal capacity of CALR del52 hematopoietic stem cells (HSCs) was comparable to that of WT HSCs. Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. Taken together, our study provides a model showing that the C-terminal of mutant CALR activated JAK-STAT signaling specifically downstream of MPL and may have a central role in CALR -induced myeloproliferative neoplasms.
doi_str_mv 10.1038/leu.2016.308
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We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic CMK11-5 cells and erythroleukemic F-36P-MPL cells with knocked-in CALR mutations showed increased growth and acquisition of cytokine-independent growth, respectively, accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation with a 52 bp deletion ( CALR del52-transgenic mice (TG)) developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow (BM) mature megakaryocytes. CALR del52 BM cells did not drive away wild-type (WT) BM cells in in vivo competitive serial transplantation assays, suggesting that the self-renewal capacity of CALR del52 hematopoietic stem cells (HSCs) was comparable to that of WT HSCs. Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. 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Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. Taken together, our study provides a model showing that the C-terminal of mutant CALR activated JAK-STAT signaling specifically downstream of MPL and may have a central role in CALR -induced myeloproliferative neoplasms.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27807369</pmid><doi>10.1038/leu.2016.308</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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issn 0887-6924
1476-5551
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5420793
source MEDLINE; Nature; SpringerLink Journals - AutoHoldings
subjects 13/31
13/44
13/95
14/28
631/67/70
64/110
692/420/755
Analysis
Animals
Calreticulin - genetics
Cancer Research
Care and treatment
Cell growth
Cell Self Renewal
Critical Care Medicine
Dosage and administration
Gastroenterology
HEK293 Cells
Hematology
Hematopoietic Stem Cells
Hemoglobin
Humans
Intensive
Internal Medicine
Janus Kinases - antagonists & inhibitors
Kinases
Leukemia
Medicine
Medicine & Public Health
Mice
Mice, Transgenic
Mutation
Myeloproliferative Disorders - chemically induced
Myeloproliferative Disorders - etiology
Oncology
Original
original-article
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Pyrazoles - pharmacology
Pyrazoles - therapeutic use
Receptors, Thrombopoietin
Ruxolitinib
STAT5 Transcription Factor - metabolism
T cells
Thrombocythemia, Essential - drug therapy
Thrombocythemia, Essential - genetics
Thrombocytosis
Transgenic animals
Tumors
White blood cell count
title Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib
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