Investigation of Stathmin 1 and microtubule instability in phenotype of hematologi...
| Full text | |
| 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]
Total Authors: 9
|
| Affiliation: | [1] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr Unicamp, Inst Nacl Ciencia & Tecnol Sangue, Sao Paulo - Brazil
Total Affiliations: 1
|
| 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: | 12/09982-8 - Investigation of molecular alterations in myeloid neoplasms |
| Grantee: | Fabíola Traina |
| Support type: | Regular Research Grants |
| 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: | 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: | 11/51959-0 - Biology of neoplastic diseases of bone marrow |
| Grantee: | Sara Teresinha Olalla Saad |
| Support type: | Research Projects - Thematic Grants |