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ULK1 Inhibition as a Targeted Therapeutic Strategy for FLT3-ITD-mutated Acute Myeloid Leukemia

Authors
 Doh Yu Hwang  ;  Ju-In Eom  ;  Ji Eun Jang  ;  Hoi-Kyung Jeung  ;  Haerim Chung  ;  Jin Seok Kim  ;  June-Won Cheong  ;  Yoo Hong Min 
Citation
 JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, Vol.39(1) : 85, 2020-05 
Journal Title
 JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 
ISSN
 0392-9078 
Issue Date
2020-05
Keywords
Acute myeloid leukemia ; Apoptosis ; Autophagy ; FLT3-ITD mutation ; ULK1
Abstract
Background: In 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. Method: We 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). Results: FLT3-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. Conclusion: ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.
Files in This Item:
T202001691.pdf Download
DOI
10.1186/s13046-020-01580-4
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Jang, Ji Eun(장지은) ORCID logo https://orcid.org/0000-0001-8832-1412
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Chung, Hae Rim(정해림) ORCID logo https://orcid.org/0000-0002-7926-9285
Hwang, Doh Yu(황도유)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/176242
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