Tags

Type your tag names separated by a space and hit enter

IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms.
Oncotarget 2016; 7(6):6948-59O

Abstract

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.

Authors+Show Affiliations

Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA. Howard Hughes Medical Institute, Portland, Oregon, USA.Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Current address: Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Current address: Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA. Howard Hughes Medical Institute, Portland, Oregon, USA.Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA. Howard Hughes Medical Institute, Portland, Oregon, USA.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Current address: Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26755644

Citation

de Melo Campos, Paula, et al. "IRS2 Silencing Increases Apoptosis and Potentiates the Effects of Ruxolitinib in JAK2V617F-positive Myeloproliferative Neoplasms." Oncotarget, vol. 7, no. 6, 2016, pp. 6948-59.
de Melo Campos P, Machado-Neto JA, Eide CA, et al. IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. Oncotarget. 2016;7(6):6948-59.
de Melo Campos, P., Machado-Neto, J. A., Eide, C. A., Savage, S. L., Scopim-Ribeiro, R., da Silva Souza Duarte, A., ... Traina, F. (2016). IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. Oncotarget, 7(6), pp. 6948-59. doi:10.18632/oncotarget.6851.
de Melo Campos P, et al. IRS2 Silencing Increases Apoptosis and Potentiates the Effects of Ruxolitinib in JAK2V617F-positive Myeloproliferative Neoplasms. Oncotarget. 2016 Feb 9;7(6):6948-59. PubMed PMID: 26755644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. AU - de Melo Campos,Paula, AU - Machado-Neto,João A, AU - Eide,Christopher A, AU - Savage,Samantha L, AU - Scopim-Ribeiro,Renata, AU - da Silva Souza Duarte,Adriana, AU - Favaro,Patricia, AU - Lorand-Metze,Irene, AU - Costa,Fernando F, AU - Tognon,Cristina E, AU - Druker,Brian J, AU - Olalla Saad,Sara T, AU - Traina,Fabiola, PY - 2015/08/05/received PY - 2016/01/01/accepted PY - 2016/1/13/entrez PY - 2016/1/13/pubmed PY - 2016/12/24/medline KW - IRS2 KW - JAK2V617F KW - STAT5 KW - apoptosis KW - myeloproliferative neoplasms SP - 6948 EP - 59 JF - Oncotarget JO - Oncotarget VL - 7 IS - 6 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26755644/IRS2_silencing_increases_apoptosis_and_potentiates_the_effects_of_ruxolitinib_in_JAK2V617F_positive_myeloproliferative_neoplasms_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=6851 DB - PRIME DP - Unbound Medicine ER -