TIFA supports NF-{kappa}B survival pathway in AML

Aurora A-dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia and other cancers, but the functional basis underlying this association is unclear. Here we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in de novo AML patients relative to healthy individuals, and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of pro-survival factors Bcl-2 and Bcl-XL that support NF-κB-dependent anti-apoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments.

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