JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL

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...

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Bibliographic Details
Published in:PloS one 2015-03, Vol.10 (3), p.e0114363-e0114363
Main Authors: Guo, Jun, Roberts, Lisa, Chen, Zhui, Merta, Philip J, Glaser, Keith B, Shah, O Jameel
Format: Article
Language:English
Subjects:
Aniline Compounds - pharmacology
Apoptosis
Bcl-2 protein
Bcl-x protein
bcl-X Protein - antagonists & inhibitors
Biotechnology
Cancer therapies
Cell Line, Tumor
Disorders
Drug Synergism
Gene Expression Regulation, Neoplastic - drug effects
Hematology
Humans
Inhibitors
Janus kinase
Janus kinase 2
Janus Kinase 2 - antagonists & inhibitors
Janus Kinase 2 - genetics
Kinases
Leukemia
Leukemia, Myeloid, Acute - pathology
Mcl-1 protein
Mutation
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Neoplasms
Neutralization
Oncology
Pathogenesis
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Proteins
R&D
Research & development
Signaling
Stat3 protein
Sulfonamides - pharmacology
Transcription
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0114363