Fighting fat in AML

Abstract

In this issue of Blood, Dany et al demonstrate a critical role of the ceramideregulated signaling pathway in inducing mitophagy to cause cell death and overcome drug resistance of acute myeloid leukemia (AML) cells carrying internal tandem duplication (ITD) of the Fms-like tyrosine kinase 3 (FLT3) gene. Ceramide is a major family member of sphingolipids and plays a key role in the response of cancer cells to chemotherapy, 8 implying that the ceramide-mediated pathway could be targeted to kill cancer cells. Ceramide is known to regulate autophagy and induce lethal mitophagy. 9 However, a mechanistic link between FLT3-ITD signaling and ceramide metabolism for the regulation of mitophagydependent cell death in AML has not been established. In this study, Dany et al reported that FLT3-ITD suppresses C 18 -ceramide generation by ceramide synthase 1 (CerS1) in AML cells, and small interfering RNA (siRNA) knockdown of FLT3-ITD or the inhibition of FLT3-ITD by a FLT3 inhibitor (such as crenolanib) induces cell death. The role of ceramide in crenolanib-induced cell death was confirmed by inhibiting CerS1 activity to reduce ceramide production, leading to resistance to TKI-induced cell death. These results indicate that alteration of ceramide synthesis provides a strategy for regulating FLI3-ITD signaling by bypassing a direct effect of a TKI on FLT3-ITD kinase.