The Class IIA Histone Deacetylase (HDAC) Inhibitor TMP269 Downregulates Ribosomal Proteins and Has Anti-Proliferative and Pro-Apoptotic Effects on AML Cells.
AML
HDAC
HDAC inhibitor
RPL6
TMP269
apoptosis
azacitidine
proliferation
venetoclax
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
07 Feb 2023
07 Feb 2023
Historique:
received:
21
11
2022
revised:
03
02
2023
accepted:
04
02
2023
entrez:
25
2
2023
pubmed:
26
2
2023
medline:
26
2
2023
Statut:
epublish
Résumé
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML patients and in different AML cell lines and (2) the effect of treating AML cells with the specific class IIA HDAC inhibitor TMP269, by applying proteomic and comparative bioinformatic analyses. We also analyzed cell proliferation, apoptosis, and the cell-killing capacities of TMP269 in combination with venetoclax compared to azacitidine plus venetoclax, by flow cytometry. Our results demonstrate significantly overexpressed class I and class II HDAC genes in AML patients, a phenotype which is conserved in AML cell lines. In AML MOLM-13 cells, TMP269 treatment downregulated a set of ribosomal proteins which are overexpressed in AML patients at the transcriptional level. TMP269 showed anti-proliferative effects and induced additive apoptotic effects in combination with venetoclax. We conclude that TMP269 exerts anti-leukemic activity when combined with venetoclax and has potential as a therapeutic drug in AML.
Identifiants
pubmed: 36831382
pii: cancers15041039
doi: 10.3390/cancers15041039
pmc: PMC9953883
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : County of Salzburg, Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : European Interreg project EPIC
ID : ITAT1054
Organisme : Austrian Science Fund (FWF)
ID : P33969
Organisme : Biomed Center Salzburg
ID : 20102-F1901165-KZP
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