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Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells

João Agostinho Machado-Neto1, Paula de Melo Campos1, Patricia Favaro1,2

  • 1Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.

Oncotarget
|September 11, 2015
PubMed

Insights

Ruxolitinib, a JAK inhibitor, activates Stathmin 1 and destabilizes microtubules in myeloproliferative neoplasms. Combining ruxolitinib with microtubule-stabilizing drugs like paclitaxel enhances apoptosis, offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The JAK/STAT pathway is crucial in myeloproliferative neoplasms (MPNs) and is targeted by ruxolitinib.
  • The JAK2(V617F) mutation drives MPNs, leading to STAT3 activation and potential Stathmin 1 inhibition.

Purpose of the Study:

  • To investigate the effect of ruxolitinib on Stathmin 1 and microtubule dynamics in JAK2(V617F)-mutated cells.
  • To explore the therapeutic potential of combining ruxolitinib with microtubule-stabilizing agents.

Main Methods:

  • Utilized HEL JAK2(V617F) cells and primary myelofibrosis patient samples.
  • Assessed protein interactions, Stathmin 1 activation, microtubule stability, cell proliferation, apoptosis, and gene expression.
  • Employed ruxolitinib, Stathmin 1 silencing, and paclitaxel treatment.

Main Results:

  • Ruxolitinib treatment decreased STAT3-Stathmin 1 association, activated Stathmin 1, and induced microtubule instability.
  • Stathmin 1 silencing reduced cell proliferation and enhanced ruxolitinib-induced apoptosis and microtubule instability.
  • Combined ruxolitinib and paclitaxel treatment significantly increased apoptosis compared to monotherapy.
  • High Stathmin 1 mRNA levels were observed in CD34(+) cells from primary myelofibrosis patients.

Conclusions:

  • Ruxolitinib treatment may inadvertently activate Stathmin 1 and destabilize microtubules in JAK2(V617F) cells.
  • Inducing microtubule stability via Stathmin 1 silencing or paclitaxel, in combination with ruxolitinib, is a promising strategy for promoting apoptosis in JAK2(V617F)-driven MPNs.
Keywords:
STAT3Stathmin 1myeloproliferative neoplasmspaclitaxelruxolitinib

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