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JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL
Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2...
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| Published in: | PloS one 2015-03, Vol.10 (3), p.e0114363-e0114363 |
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| creator | Guo, Jun Roberts, Lisa Chen, Zhui Merta, Philip J Glaser, Keith B Shah, O Jameel |
| description | Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations. |
| doi_str_mv | 10.1371/journal.pone.0114363 |
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We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0114363</identifier><identifier>PMID: 25781882</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aniline Compounds - pharmacology ; Apoptosis ; Bcl-2 protein ; Bcl-x protein ; bcl-X Protein - antagonists & inhibitors ; Biotechnology ; Cancer therapies ; Cell Line, Tumor ; Disorders ; Drug Synergism ; Gene Expression Regulation, Neoplastic - drug effects ; Hematology ; Humans ; Inhibitors ; Janus kinase ; Janus kinase 2 ; Janus Kinase 2 - antagonists & inhibitors ; Janus Kinase 2 - genetics ; Kinases ; Leukemia ; Leukemia, Myeloid, Acute - pathology ; Mcl-1 protein ; Mutation ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Neoplasms ; Neutralization ; Oncology ; Pathogenesis ; Phosphorylation ; Protein Kinase Inhibitors - pharmacology ; Proteins ; R&D ; Research & development ; Signaling ; Stat3 protein ; Sulfonamides - pharmacology ; Transcription ; Tumors</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0114363-e0114363</ispartof><rights>2015 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Guo et al 2015 Guo et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4373-6b582726d7e0de4fbbf195091279228e3ab04202426f31049fa83d31d4aae543</citedby><cites>FETCH-LOGICAL-c4373-6b582726d7e0de4fbbf195091279228e3ab04202426f31049fa83d31d4aae543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1664227718/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1664227718?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25781882$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bunting, Kevin D</contributor><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Roberts, Lisa</creatorcontrib><creatorcontrib>Chen, Zhui</creatorcontrib><creatorcontrib>Merta, Philip J</creatorcontrib><creatorcontrib>Glaser, Keith B</creatorcontrib><creatorcontrib>Shah, O Jameel</creatorcontrib><title>JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.</description><subject>Aniline Compounds - pharmacology</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Bcl-x protein</subject><subject>bcl-X Protein - antagonists & inhibitors</subject><subject>Biotechnology</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Disorders</subject><subject>Drug Synergism</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Hematology</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Janus kinase</subject><subject>Janus kinase 2</subject><subject>Janus Kinase 2 - antagonists & inhibitors</subject><subject>Janus Kinase 2 - genetics</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Mcl-1 protein</subject><subject>Mutation</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - 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We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25781882</pmid><doi>10.1371/journal.pone.0114363</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Aniline Compounds - pharmacology Apoptosis Bcl-2 protein Bcl-x protein bcl-X Protein - antagonists & inhibitors Biotechnology Cancer therapies Cell Line, Tumor Disorders Drug Synergism Gene Expression Regulation, Neoplastic - drug effects Hematology Humans Inhibitors Janus kinase Janus kinase 2 Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - genetics Kinases Leukemia Leukemia, Myeloid, Acute - pathology Mcl-1 protein Mutation Myeloid Cell Leukemia Sequence 1 Protein - metabolism Neoplasms Neutralization Oncology Pathogenesis Phosphorylation Protein Kinase Inhibitors - pharmacology Proteins R&D Research & development Signaling Stat3 protein Sulfonamides - pharmacology Transcription Tumors |
| title | JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL |
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