Abstract 3123: Identification of TIFA as a novel therapeutic target in acute myeloid leukemia

Abstract

Abstract Aurora A-dependent NF-κB signaling portends poor prognosis of cancers including acute myeloid leukemia (AML). Our previous study demonstrated that phosphorylation-dependent oligomerization of TRAF-interacting protein with FHA domain (TIFA) triggers the activation of NF-κB. The present study identifies that Aurora A is an essential kinase for the Thr9 phosphorylation of TIFA, and that TIFA functionally mediates the Aurora A-driven NF-κB survival pathway in AML. Overexpression of TIFA occurred concurrently with Aurora A and NF-κB signaling factors in de novo AML patients but not healthy individuals, and also correlated with poor prognosis. Silencing of TIFA specifically attenuated leukemic cell growth and enhanced chemosensitivity of AML cells via down-regulation of pro-survival factors Bcl-2 and Bcl-XL that support NF-κB-dependent anti-apoptotic events. In addition, molecular targeting of TIFA perturbed leukemic cytokine secretion and significantly lowered the IC50 of chemotherapeutic drugs to treat AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiates the clearance of leukemic myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity, similar to the effect of anti-inflammatory drug treatments. Collectively, we proposed that TIFA functionally supports the positive feedback between TNF-α, Aurora A, and NF-κB to facilitate AML survival signaling, and impairment in this pathway can enhance the efficacy of AML treatments. Citation Format: Pei-Yu Wu, Tong-You Wade Wei, Ting-Jung Wu, Ming-Daw Tsai. Identification of TIFA as a novel therapeutic target in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3123. doi:10.1158/1538-7445.AM2017-3123