JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL.
PLoS One
; 10(3): e0114363, 2015.
Article
em En
| MEDLINE
| ID: mdl-25781882
ABSTRACT
Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.
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Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
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Regulação Neoplásica da Expressão Gênica
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Proteína bcl-X
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Janus Quinase 2
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Proteína de Sequência 1 de Leucemia de Células Mieloides
/
Mutação
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article