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 |