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 and STAT5 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 acute leukemia 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.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 12. doi:10.1158/1538-7445.AM2011-12