Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia.
Acute Disease
Adamantane
/ analogs & derivatives
Adult
Biomarkers, Tumor
/ genetics
Cell Line, Tumor
Cell Survival
/ drug effects
Cytoskeletal Proteins
/ antagonists & inhibitors
Cytoskeleton
/ metabolism
Disease-Free Survival
Female
Gene Expression Regulation, Leukemic
Genes, Regulator
/ genetics
HL-60 Cells
Humans
K562 Cells
Leukemia, Myeloid
/ diagnosis
Male
Phenols
/ pharmacology
Prognosis
Quinolines
/ pharmacology
Quinolones
/ pharmacology
THP-1 Cells
U937 Cells
Acute myeloid leukemia
Antineoplastic agents
Cytoskeleton
Ezrin
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
08
03
2021
accepted:
11
06
2021
pubmed:
2
7
2021
medline:
8
2
2022
entrez:
1
7
2021
Statut:
ppublish
Résumé
Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells. From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs.
Identifiants
pubmed: 34196912
doi: 10.1007/s13402-021-00621-0
pii: 10.1007/s13402-021-00621-0
doi:
Substances chimiques
Biomarkers, Tumor
0
Cytoskeletal Proteins
0
NSC305787
0
NSC668394
0
Phenols
0
Quinolines
0
Quinolones
0
ezrin
0
Adamantane
PJY633525U
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1105-1117Subventions
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : #2017/24993-0
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : #2019/23864-7
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : #2015/17177-6
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : Finance Code 001
Informations de copyright
© 2021. Springer Nature Switzerland AG.
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