Abstract
BackgroundIn acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target for various cancers, its role in FLT3-ITD AML remains elusive. In this study, we evaluated the effects of ULK1 inhibition on leukemia cell death in FLT3-ITD AML.MethodWe evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc).ResultsFLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors.ConclusionULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.
Highlights
In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome
Effects of uncoordinated 51-like kinase 1 (ULK1) inhibitors on apoptosis in FLT3-ITD AML We assessed the effect of ULK1 inhibitor treatment relative to that of DMSO as a control, on the induction of cell death in a panel of leukemic cell lines harboring FLT3-ITD mutations or not over a 48-h time course
The findings that high levels of ULK1 are associated with poor prognosis in several solid tumors [28, 37] and that ULK1 inhibition can rescue the phenotype induced by caspase-3 deletion in AML1/ETO AML cells [38] suggest that ULK1 is a promising new therapeutic target for cancers
Summary
In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia (AML) accounts for up to 30% of adult AML cases, and the prognosis of patients with FLT3-ITD-mutated AML is Several FLT3 tyrosine kinase inhibitors (TKIs) have been developed to target the aberrantly activated FLT3. Mutational analysis of samples from patients who had relapsed after FLT3-TKI treatment, as well as data from preclinical studies suggest that a cellular adaptive mechanism involving the activation of signaling pathways plays a role in the FLT3-TKI resistance pathway [8], these pathways remain poorly elucidated.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
