Irs2 Silencing Increases Apoptosis And Potentiates The Effects Of Ruxolitinib In Jak2(v617f)-positive Myeloproliferative Neoplasms

dc.creatorCampos
dc.creatorPaula de Melo; Machado-Neto
dc.creatorJoao A.; Eide
dc.creatorChristopher A.; Savage
dc.creatorSamantha L.; Scopim-Ribeiro
dc.creatorRenata; Souza Duarte
dc.creatorAdriana da Silva; Favaro
dc.creatorPatricia; Lorand-Metze
dc.creatorIrene; Costa
dc.creatorFernando F.; Tognon
dc.creatorCristina E.; Druker
dc.creatorBrian J.; Olalla Saad
dc.creatorSara T.; Traina
dc.creatorFabiola
dc.date2016
dc.datefev
dc.date2017-11-13T13:43:30Z
dc.date2017-11-13T13:43:30Z
dc.date.accessioned2018-03-29T05:58:12Z
dc.date.available2018-03-29T05:58:12Z
dc.identifierOncotarget. Impact Journals Llc, v. 7, p. 6948 - 6959, 2016.
dc.identifier1949-2553
dc.identifierWOS:000376123100042
dc.identifier10.18632/oncotarget.6851
dc.identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872760/
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/328566
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1365591
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionThe recurrent V617F mutation in JAK2 (JAK2(V617F)) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2(V617F) HEL cells, but not in the JAK2(WT) U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2(V617F)-positive but not JAK2(WT) specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34(+) cells from essential thrombocythemia patients compared to healthy donors, and in JAK2(V617F) MPN patients when compared to JAK2(WT). Our data indicate that IRS2 is a binding partner of JAK2(V617F) in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN.
dc.description7
dc.description6
dc.description6948
dc.description6959
dc.descriptionNational Council of Technological and Scientific Development (CNPq)
dc.descriptionInstituto Nacional de Ciencia e Tecnologia do Sangue (INCTS)
dc.descriptionSao Paulo Research Foundation (FAPESP)
dc.descriptionHoward Hughes Medical Institute
dc.descriptionLeukemia and Lymphoma Society: Specialized Center of Research [7005-11]
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.languageEnglish
dc.publisherImpact Journals Llc
dc.publisherAlbany
dc.relationOncotarget
dc.rightsaberto
dc.sourceWOS
dc.subjectIrs2
dc.subjectJak2(v617f)
dc.subjectStat5
dc.subjectMyeloproliferative Neoplasms
dc.subjectApoptosis
dc.titleIrs2 Silencing Increases Apoptosis And Potentiates The Effects Of Ruxolitinib In Jak2(v617f)-positive Myeloproliferative Neoplasms
dc.typeArtículos de revistas


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