Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/328566
Type: Artigo
Title: Irs2 Silencing Increases Apoptosis And Potentiates The Effects Of Ruxolitinib In Jak2(v617f)-positive Myeloproliferative Neoplasms
Author: Campos
Paula de Melo; Machado-Neto
Joao A.; Eide
Christopher A.; Savage
Samantha L.; Scopim-Ribeiro
Renata; Souza Duarte
Adriana da Silva; Favaro
Patricia; Lorand-Metze
Irene; Costa
Fernando F.; Tognon
Cristina E.; Druker
Brian J.; Olalla Saad
Sara T.; Traina
Fabiola
Abstract: The 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.
Subject: Irs2
Jak2(v617f)
Stat5
Myeloproliferative Neoplasms
Apoptosis
Editor: Impact Journals Llc
Albany
Citation: Oncotarget. Impact Journals Llc, v. 7, p. 6948 - 6959, 2016.
Rights: aberto
Identifier DOI: 10.18632/oncotarget.6851
Address: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872760/
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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