title: JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL.
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.
authors.affiliation: Oncology Division, Research & Development, AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Oncology Division, Research & Development, AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Roberts
authors.affiliation: Oncology Division, Research & Development, AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: Zhui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Oncology Division, Research & Development, AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.affiliation: Oncology Division, Research & Development, AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.affiliation: Oncology Division, Research & Development, AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: O Jameel
authors.initials: OJ
authors.lastname: Shah
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D051020:bcl-X Protein; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C528561:navitoclax