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...
Gespeichert in:
Veröffentlicht in: | Leukemia 2017-05, Vol.31 (5), p.1136-1144 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
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 |
format | Article |
fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5420793</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A491080025</galeid><sourcerecordid>A491080025</sourcerecordid><originalsourceid>FETCH-LOGICAL-c581t-a6872a83f062966399bb51a5d9dd965cfc316a66d2e607408fd83d51574c092d3</originalsourceid><addsrcrecordid>eNptks-L3CAUx0Np6U63vfVchELpoZlqjEYvC8PQ3wu9tGcxaiYuRqdqls5_X8NstzNl8SC-93lf-T6-VfUSwTWCmL13Zl43ENE1huxRtUJtR2tCCHpcrSBjXU15015Uz1K6gXBp0qfVRdMx2GHKV1XYShdNtmp21oNpztJnMFllgDa3xoU9MCkZn610II8xTH1QhzyaycrylhnYBORknA1RZqNBfyhlA75uvgHrR9vbHCKI8-_gbLbe9s-rJ4N0yby4uy-rnx8__Nh-rq-_f_qy3VzXijCUa0lZ10iGB0gbTinmvO8JkkRzrTklalAYUUmpbgyFXQvZoBnWBJGuVZA3Gl9WV0fd_dxPRqtiIUon9tFOMh5EkFacd7wdxS7cCtI2sOO4CLy9E4jh12xSFpNNyjgnvQlzEohD1LW4xbygr_9Db8IcfbEnEOMto5gw8o_aSWeE9UMo_6pFVGxajiCDsFmo9QNUObqsXAVvBlvqZwNvTgZGI10eU3BztsGnc_DdEVQxpBTNcL8MBMWSJFGSJJYkiZKkgr86XeA9_Dc6BaiPQCotvzPxxPVDgn8ALtDSpw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1894863585</pqid></control><display><type>article</type><title>Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib</title><source>MEDLINE</source><source>Nature</source><source>SpringerLink Journals - AutoHoldings</source><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</creator><creatorcontrib>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</creatorcontrib><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.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2016.308</identifier><identifier>PMID: 27807369</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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</subject><ispartof>Leukemia, 2017-05, Vol.31 (5), p.1136-1144</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c581t-a6872a83f062966399bb51a5d9dd965cfc316a66d2e607408fd83d51574c092d3</citedby><cites>FETCH-LOGICAL-c581t-a6872a83f062966399bb51a5d9dd965cfc316a66d2e607408fd83d51574c092d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2016.308$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2016.308$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27807369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shide, K</creatorcontrib><creatorcontrib>Kameda, T</creatorcontrib><creatorcontrib>Yamaji, T</creatorcontrib><creatorcontrib>Sekine, M</creatorcontrib><creatorcontrib>Inada, N</creatorcontrib><creatorcontrib>Kamiunten, A</creatorcontrib><creatorcontrib>Akizuki, K</creatorcontrib><creatorcontrib>Nakamura, K</creatorcontrib><creatorcontrib>Hidaka, T</creatorcontrib><creatorcontrib>Kubuki, Y</creatorcontrib><creatorcontrib>Shimoda, H</creatorcontrib><creatorcontrib>Kitanaka, A</creatorcontrib><creatorcontrib>Honda, A</creatorcontrib><creatorcontrib>Sawaguchi, A</creatorcontrib><creatorcontrib>Abe, H</creatorcontrib><creatorcontrib>Miike, T</creatorcontrib><creatorcontrib>Iwakiri, H</creatorcontrib><creatorcontrib>Tahara, Y</creatorcontrib><creatorcontrib>Sueta, M</creatorcontrib><creatorcontrib>Hasuike, S</creatorcontrib><creatorcontrib>Yamamoto, S</creatorcontrib><creatorcontrib>Nagata, K</creatorcontrib><creatorcontrib>Shimoda, K</creatorcontrib><title>Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><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.</description><subject>13/31</subject><subject>13/44</subject><subject>13/95</subject><subject>14/28</subject><subject>631/67/70</subject><subject>64/110</subject><subject>692/420/755</subject><subject>Analysis</subject><subject>Animals</subject><subject>Calreticulin - genetics</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell growth</subject><subject>Cell Self Renewal</subject><subject>Critical Care Medicine</subject><subject>Dosage and administration</subject><subject>Gastroenterology</subject><subject>HEK293 Cells</subject><subject>Hematology</subject><subject>Hematopoietic Stem Cells</subject><subject>Hemoglobin</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Janus Kinases - antagonists & inhibitors</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Myeloproliferative Disorders - chemically induced</subject><subject>Myeloproliferative Disorders - etiology</subject><subject>Oncology</subject><subject>Original</subject><subject>original-article</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrazoles - therapeutic use</subject><subject>Receptors, Thrombopoietin</subject><subject>Ruxolitinib</subject><subject>STAT5 Transcription Factor - metabolism</subject><subject>T cells</subject><subject>Thrombocythemia, Essential - drug therapy</subject><subject>Thrombocythemia, Essential - genetics</subject><subject>Thrombocytosis</subject><subject>Transgenic animals</subject><subject>Tumors</subject><subject>White blood cell count</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptks-L3CAUx0Np6U63vfVchELpoZlqjEYvC8PQ3wu9tGcxaiYuRqdqls5_X8NstzNl8SC-93lf-T6-VfUSwTWCmL13Zl43ENE1huxRtUJtR2tCCHpcrSBjXU15015Uz1K6gXBp0qfVRdMx2GHKV1XYShdNtmp21oNpztJnMFllgDa3xoU9MCkZn610II8xTH1QhzyaycrylhnYBORknA1RZqNBfyhlA75uvgHrR9vbHCKI8-_gbLbe9s-rJ4N0yby4uy-rnx8__Nh-rq-_f_qy3VzXijCUa0lZ10iGB0gbTinmvO8JkkRzrTklalAYUUmpbgyFXQvZoBnWBJGuVZA3Gl9WV0fd_dxPRqtiIUon9tFOMh5EkFacd7wdxS7cCtI2sOO4CLy9E4jh12xSFpNNyjgnvQlzEohD1LW4xbygr_9Db8IcfbEnEOMto5gw8o_aSWeE9UMo_6pFVGxajiCDsFmo9QNUObqsXAVvBlvqZwNvTgZGI10eU3BztsGnc_DdEVQxpBTNcL8MBMWSJFGSJJYkiZKkgr86XeA9_Dc6BaiPQCotvzPxxPVDgn8ALtDSpw</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Shide, K</creator><creator>Kameda, T</creator><creator>Yamaji, T</creator><creator>Sekine, M</creator><creator>Inada, N</creator><creator>Kamiunten, A</creator><creator>Akizuki, K</creator><creator>Nakamura, K</creator><creator>Hidaka, T</creator><creator>Kubuki, Y</creator><creator>Shimoda, H</creator><creator>Kitanaka, A</creator><creator>Honda, A</creator><creator>Sawaguchi, A</creator><creator>Abe, H</creator><creator>Miike, T</creator><creator>Iwakiri, H</creator><creator>Tahara, Y</creator><creator>Sueta, M</creator><creator>Hasuike, S</creator><creator>Yamamoto, S</creator><creator>Nagata, K</creator><creator>Shimoda, K</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20170501</creationdate><title>Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c581t-a6872a83f062966399bb51a5d9dd965cfc316a66d2e607408fd83d51574c092d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/31</topic><topic>13/44</topic><topic>13/95</topic><topic>14/28</topic><topic>631/67/70</topic><topic>64/110</topic><topic>692/420/755</topic><topic>Analysis</topic><topic>Animals</topic><topic>Calreticulin - genetics</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Cell growth</topic><topic>Cell Self Renewal</topic><topic>Critical Care Medicine</topic><topic>Dosage and administration</topic><topic>Gastroenterology</topic><topic>HEK293 Cells</topic><topic>Hematology</topic><topic>Hematopoietic Stem Cells</topic><topic>Hemoglobin</topic><topic>Humans</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Janus Kinases - antagonists & inhibitors</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>Myeloproliferative Disorders - chemically induced</topic><topic>Myeloproliferative Disorders - etiology</topic><topic>Oncology</topic><topic>Original</topic><topic>original-article</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrazoles - therapeutic use</topic><topic>Receptors, Thrombopoietin</topic><topic>Ruxolitinib</topic><topic>STAT5 Transcription Factor - metabolism</topic><topic>T cells</topic><topic>Thrombocythemia, Essential - drug therapy</topic><topic>Thrombocythemia, Essential - genetics</topic><topic>Thrombocytosis</topic><topic>Transgenic animals</topic><topic>Tumors</topic><topic>White blood cell count</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shide, K</creatorcontrib><creatorcontrib>Kameda, T</creatorcontrib><creatorcontrib>Yamaji, T</creatorcontrib><creatorcontrib>Sekine, M</creatorcontrib><creatorcontrib>Inada, N</creatorcontrib><creatorcontrib>Kamiunten, A</creatorcontrib><creatorcontrib>Akizuki, K</creatorcontrib><creatorcontrib>Nakamura, K</creatorcontrib><creatorcontrib>Hidaka, T</creatorcontrib><creatorcontrib>Kubuki, Y</creatorcontrib><creatorcontrib>Shimoda, H</creatorcontrib><creatorcontrib>Kitanaka, A</creatorcontrib><creatorcontrib>Honda, A</creatorcontrib><creatorcontrib>Sawaguchi, A</creatorcontrib><creatorcontrib>Abe, H</creatorcontrib><creatorcontrib>Miike, T</creatorcontrib><creatorcontrib>Iwakiri, H</creatorcontrib><creatorcontrib>Tahara, Y</creatorcontrib><creatorcontrib>Sueta, M</creatorcontrib><creatorcontrib>Hasuike, S</creatorcontrib><creatorcontrib>Yamamoto, S</creatorcontrib><creatorcontrib>Nagata, K</creatorcontrib><creatorcontrib>Shimoda, K</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shide, K</au><au>Kameda, T</au><au>Yamaji, T</au><au>Sekine, M</au><au>Inada, N</au><au>Kamiunten, A</au><au>Akizuki, K</au><au>Nakamura, K</au><au>Hidaka, T</au><au>Kubuki, Y</au><au>Shimoda, H</au><au>Kitanaka, A</au><au>Honda, A</au><au>Sawaguchi, A</au><au>Abe, H</au><au>Miike, T</au><au>Iwakiri, H</au><au>Tahara, Y</au><au>Sueta, M</au><au>Hasuike, S</au><au>Yamamoto, S</au><au>Nagata, K</au><au>Shimoda, K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>31</volume><issue>5</issue><spage>1136</spage><epage>1144</epage><pages>1136-1144</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>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.</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> |
fulltext | fulltext |
identifier | ISSN: 0887-6924 |
ispartof | Leukemia, 2017-05, Vol.31 (5), p.1136-1144 |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T13%3A40%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Calreticulin%20mutant%20mice%20develop%20essential%20thrombocythemia%20that%20is%20ameliorated%20by%20the%20JAK%20inhibitor%20ruxolitinib&rft.jtitle=Leukemia&rft.au=Shide,%20K&rft.date=2017-05-01&rft.volume=31&rft.issue=5&rft.spage=1136&rft.epage=1144&rft.pages=1136-1144&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2016.308&rft_dat=%3Cgale_pubme%3EA491080025%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1894863585&rft_id=info:pmid/27807369&rft_galeid=A491080025&rfr_iscdi=true |