title: Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells.
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.
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: João Agostinho
authors.initials: JA
authors.lastname: Machado-Neto
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Paula
authors.initials: P
authors.lastname: de Melo Campos
authors.affiliation: 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Favaro
authors.affiliation: 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.
authors.forename: Mariana
authors.initials: M
authors.lastname: Lazarini
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: da Silva Santos Duarte
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Irene
authors.initials: I
authors.lastname: Lorand-Metze
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Sara Teresinha Olalla
authors.initials: ST
authors.lastname: Saad
authors.affiliation: 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.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D008875:Middle Aged; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism; D009570:Nitriles; D017239:Paclitaxel / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D055815:Young Adult
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C493995:STMN1 protein, human; D050777:Stathmin; D050257:Tubulin Modulators; C540383:ruxolitinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D017239:Paclitaxel
keywords: STAT3; Stathmin 1; myeloproliferative neoplasms; paclitaxel; ruxolitinib