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

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

Author Campos, Paula de Melo Google Scholar
Machado-Neto, Joao A. Google Scholar
Eide, Christopher A. Google Scholar
Savage, Samantha L. Google Scholar
Scopim-Ribeiro, Renata Google Scholar
Souza Duarte, Adriana da Silva Google Scholar
Favaro, Patricia Autor UNIFESP Google Scholar
Lorand-Metze, Irene Google Scholar
Costa, Fernando F. Google Scholar
Tognon, Cristina E. Google Scholar
Druker, Brian J. Google Scholar
Olalla Saad, Sara T. Google Scholar
Traina, Fabiola Google Scholar
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.
Keywords IRS2
JAK2(V617F)
STAT5
myeloproliferative neoplasms
apoptosis
xmlui.dri2xhtml.METS-1.0.item-coverage Albany
Language English
Sponsor National Council of Technological and Scientific Development (CNPq)
Instituto Nacional de Ciencia e Tecnologia do Sangue (INCTS)
Sao Paulo Research Foundation (FAPESP)
Howard Hughes Medical Institute
Leukemia and Lymphoma Society: Specialized Center of Research
Grant number Leukemia and Lymphoma Society: Specialized Center of Research : 7005-11
Date 2016
Published in Oncotarget. Albany, v. 7, n. 6, p. 6948-6959, 2016.
ISSN 1949-2553 (Sherpa/Romeo, impact factor)
Publisher Impact Journals Llc
Extent 6948-6959
Origin http://dx.doi.org/10.18632/oncotarget.6851
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000376123100042
URI https://repositorio.unifesp.br/handle/11600/57977

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