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

PloS One
Jun GuoO Jameel Shah

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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Citations

Jan 27, 2016·Proceedings of the National Academy of Sciences of the United States of America·Wei JuThomas A Waldmann
Feb 19, 2016·Journal of Immunoassay & Immunochemistry·Cristina MambetCarmen C Diaconu
Jul 10, 2019·Investigational New Drugs·João Agostinho Machado-NetoFabiola Traina
Jul 11, 2019·Scientific Reports·Keli LimaJoão Agostinho Machado-Neto
Aug 18, 2020·Leukemia & Lymphoma·Raquel TognonFabíola Attié de Castro
Jul 19, 2017·The Journal of Biological Chemistry·Lauren M BrownPaul G Ekert
Apr 13, 2021·Expert Opinion on Therapeutic Targets·Erika Morsia, Naseema Gangat

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Datasets Mentioned

BETA
ABT-263

Methods Mentioned

BETA
Transfection
ChIP
immunoprecipitation
PCR
xenograft
two hybrid

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