IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2(V617F)-positive myeloproliferative neoplasms

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dc.citation.issue6
dc.citation.volume7
dc.contributor.authorCampos, Paula de Melo
dc.contributor.authorMachado-Neto, Joao A.
dc.contributor.authorEide, Christopher A.
dc.contributor.authorSavage, Samantha L.
dc.contributor.authorScopim-Ribeiro, Renata
dc.contributor.authorSouza Duarte, Adriana da Silva
dc.contributor.authorFavaro, Patricia [UNIFESP]
dc.contributor.authorLorand-Metze, Irene
dc.contributor.authorCosta, Fernando F.
dc.contributor.authorTognon, Cristina E.
dc.contributor.authorDruker, Brian J.
dc.contributor.authorOlalla Saad, Sara T.
dc.contributor.authorTraina, Fabiola
dc.coverageAlbany
dc.date.accessioned2020-08-21T17:00:24Z
dc.date.available2020-08-21T17:00:24Z
dc.date.issued2016
dc.description.abstractThe 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.en
dc.description.affiliationUniv Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr, UNICAMP,Inst Nacl Ciencia & Tecnol Sangue, Campinas, SP, Brazil
dc.description.affiliationOregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA
dc.description.affiliationHoward Hughes Med Inst, Portland, OR USA
dc.description.affiliationUniv Fed Sao Paulo, Dept Biol Sci, Diadema, SP, Brazil
dc.description.affiliationUniv Sao Paulo Ribeirao Preto, Sch Med, Dept Internal Med, Ribeirao Preto, SP, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Biol Sci, Diadema, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipNational Council of Technological and Scientific Development (CNPq)
dc.description.sponsorshipInstituto Nacional de Ciencia e Tecnologia do Sangue (INCTS)
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP)
dc.description.sponsorshipHoward Hughes Medical Institute
dc.description.sponsorshipLeukemia and Lymphoma Society: Specialized Center of Research
dc.description.sponsorshipIDLeukemia and Lymphoma Society: Specialized Center of Research : 7005-11
dc.format.extent6948-6959
dc.identifierhttp://dx.doi.org/10.18632/oncotarget.6851
dc.identifier.citationOncotarget. Albany, v. 7, n. 6, p. 6948-6959, 2016.
dc.identifier.doi10.18632/oncotarget.6851
dc.identifier.issn1949-2553
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/57977
dc.identifier.wosWOS:000376123100042
dc.language.isoeng
dc.publisherImpact Journals Llc
dc.relation.ispartofOncotarget
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectIRS2en
dc.subjectJAK2(V617F)en
dc.subjectSTAT5en
dc.subjectmyeloproliferative neoplasmsen
dc.subjectapoptosisen
dc.titleIRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2(V617F)-positive myeloproliferative neoplasmsen
dc.typeinfo:eu-repo/semantics/article
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