IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms
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Paula de Melo Campos1, João A. Machado-Neto1, Christopher A. Eide2,3, Samantha L. Savage2, Renata Scopim-Ribeiro1,5, Adriana da Silva Souza Duarte1, Patricia Favaro1,4, Irene Lorand-Metze1, Fernando F. Costa1, Cristina E. Tognon2,3, Brian J. Druker2,3, Sara T. Olalla Saad1, Fabiola Traina1,5
1Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil
2Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
3Howard Hughes Medical Institute, Portland, Oregon, USA
4Current address: Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil
5Current address: Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil
Keywords: IRS2, JAK2V617F, STAT5, myeloproliferative neoplasms, apoptosis
Received: August 05, 2015 Accepted: January 01, 2016 Published: January 09, 2016
The recurrent V617F mutation in JAK2 (JAK2V617F) 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 JAK2V617F HEL cells, but not in the JAK2WT 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 JAK2V617F-positive but not JAK2WT 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 JAK2V617F MPN patients when compared to JAK2WT. Our data indicate that IRS2 is a binding partner of JAK2V617F 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.
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