RRC ID 82579
Author Nogami A, Amemiya HJ, Fujiwara H, Umezawa Y, Tohda S, Nagao T.
Title Targeting USP14/UCHL5: A Breakthrough Approach to Overcoming Treatment-Resistant FLT3-ITD-Positive AML.
Journal Int J Mol Sci
Abstract FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) are associated with poor prognosis and therapy resistance. This study aimed to demonstrate that inhibiting the deubiquitinating enzymes ubiquitin-specific peptidase 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5) (USP14/UCHL5) with b-AP15 or the organogold compound auranofin (AUR) induces apoptosis in the ITD-transformed human leukemia cell line MV4-11 and mononuclear leukocytes derived from patients with FLT3-ITD-positive AML. This study included patients diagnosed with AML at Tokyo Medical and Dental University Hospital between January 2018 and July 2024. Both treatments blocked downstream FLT3 pathway events, with the effects potentiated by USP14 knockdown. Both treatments inhibited FLT3 deubiquitination via K48 and disrupted translation initiation via 4EBP1, a downstream FLT3 target. FLT3 was downregulated in the leukemic cells, with the associated activation of stress-related MAP kinase pathways and increased NF-E2-related factor 2. Furthermore, the overexpression of B-cell lymphoma-extra-large and myeloid cell leukemia-1 prevented the cell death caused by b-AP15 and AUR. These results suggest that inhibiting USP14/UCHL5, which involves multiple regulatory mechanisms, is a promising target for novel therapies for treatment-resistant FLT3-ITD-positive AML.
Volume 25(19)
Published 2024-9-26
DOI 10.3390/ijms251910372
PII ijms251910372
PMID 39408703
PMC PMC11476563
MeSH Adult Aged Apoptosis / drug effects Cell Line, Tumor Drug Resistance, Neoplasm* / drug effects Drug Resistance, Neoplasm* / genetics Female Humans Leukemia, Myeloid, Acute* / drug therapy Leukemia, Myeloid, Acute* / genetics Leukemia, Myeloid, Acute* / metabolism Leukemia, Myeloid, Acute* / pathology Male Middle Aged Mutation Ubiquitin Thiolesterase* / antagonists & inhibitors Ubiquitin Thiolesterase* / genetics Ubiquitin Thiolesterase* / metabolism fms-Like Tyrosine Kinase 3* / genetics fms-Like Tyrosine Kinase 3* / metabolism
IF 4.556
Resource
Human and Animal Cells K562 U937