Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2(V617F) cells

Author(s)

Machado-Neto, Joao Agostinho ^[1] ; Campos, Paula de Melo ^[1] ; Favaro, Patricia ^[1] ; Lazarini, Mariana ^[1] ; Santos Duarte, Adriana da Silva ^[1] ; Lorand-Metze, Irene ^[1] ; Costa, Fernando Ferreira ^[1] ; Olalla Saad, Sara Teresinha ^[1] ; Traina, Fabiola ^[1]

Affiliation

^[1] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr Unicamp, Inst Nacl Ciencia & Tecnol Sangue, Sao Paulo - Brazil

• Document type: Journal article
• Source: ONCOTARGET; v. 6, n. 30, p. 29573-29584, OCT 6 2015.
• Web of Science Citations: 7

Abstract

The JAK/STAT pathway is constitutively activated in myeloproliferative neoplasms and can be inhibited by ruxolitinib, a selective JAK1/2 inhibitor. The JAK2(V617F) mutation leads to constitutive STAT3 phosphorylation and potentially leads to inhibition of Stathmin 1 activity via STAT3. In support of this hypothesis, we found that, in HEL JAK2(V617F) cells, ruxolitinib treatment decreased STAT3 and Stathmin 1 association, induced Stathmin 1 activation and microtubule instability. Silencing of Stathmin 1 significantly reduced cell proliferation and clonal growth, and increased apoptosis induced by ruxolitinib. Stathmin 1 silencing also prevented ruxolitinib-induced microtubule instability. To phenocopy the effect of Stathmin 1 inhibition, cells were treated with paclitaxel, a microtubule-stabilizing drug, in association or not with ruxolitinib; combined treatment significantly increased apoptosis, when compared to monotherapy. Notably, Stathmin 1 mRNA levels were highly expressed in CD34(+) cells from primary myelofibrosis patients. We then proposed that an undesired effect of ruxolitinib treatment may constitute Stathmin 1 activation and microtubule instability in JAK2(V617F) cells. Induction of microtubule stability, through Stathmin 1 silencing or paclitaxel treatment, combined with ruxolitinib could be an effective strategy for promoting apoptosis in JAK2(V617F) cells. (AU)

• FAPESP's process: 11/51959-0 - Biology of neoplastic diseases of bone marrow
• Grantee: Sara Teresinha Olalla Saad
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 11/06840-5 - Study of ANKHD1 function on the proliferation, apoptosis and cell cycle in hematological neoplasia
• Grantee: João Agostinho Machado Neto
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/23092-0 - Investigation of IRS2 protein function in hematopoietic cells
• Grantee: João Agostinho Machado Neto
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/09982-8 - Investigation of molecular alterations in myeloid neoplasms.
• Grantee: Fabíola Traina
• Support type: Regular Research Grants