Abstract B35: FLT3-TAZ signaling induces drug resistance in leukemia

Abstract

Abstract YAP/TAZ, the transcriptional coactivators of TEAD and major transducers of the Hippo pathway, has been studied only in solid tumors. Interestingly, YAP/TAZ are consistently upregulated in adherent tumor cell lines, but hardly expressed in hematologic malignancies including lymphoma and leukemia. However, we identified significant upregulation of TAZ in specific leukemia mouse models driven by FLT3 (AML) or Bcr-Abl (blast crisis-CML; bc-CML). We observed strong correlation between TAZ and FLT3 induction in bc-CML patients as well as leukemia cells, which led us to investigate the role of FLT3-TAZ signaling in imatinib-induced drug resistance in CML. FLT3 expression induced imatinib resistance (IR) in K562 CML cells. In K562-IR cells, transcription of TAZ mRNA is significantly increased, but not YAP. Our data show that target gene induction by TAZ-TEAD interaction promotes imatinib resistance. Importantly, inhibition of FLT3-TAZ signaling resensitized K562-IR cell to imatinib treatment and caused cell death. Therefore, we propose that combination therapy targeting both FLT3-TAZ and Bcr/abl signaling could trigger synthetic lethality in bc-CML cells. Citation Format: Ji Eun Shin, Hyun Woo Park. FLT3-TAZ signaling induces drug resistance in leukemia [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B35.