Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia.
Azacitidine
/ therapeutic use
Chemokine CXCL12
/ metabolism
Combined Modality Therapy
Cyclopentanes
/ pharmacology
HL-60 Cells
Humans
Leukemia, Myeloid, Acute
/ genetics
NEDD8 Protein
/ metabolism
Pre-B-Cell Leukemia Transcription Factor 1
/ metabolism
Pyrimidines
/ pharmacology
RNA Interference
Signal Transduction
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 12 2021
02 12 2021
Historique:
received:
22
06
2021
accepted:
08
11
2021
entrez:
3
12
2021
pubmed:
4
12
2021
medline:
28
1
2022
Statut:
epublish
Résumé
Treatment of acute myeloid leukemia (AML) remains challenging and novel targets and synergistic therapies still need to be discovered. We performed a high-throughput RNAi screen in three different AML cell lines and primary human leukemic blasts to identify genes that synergize with common antileukemic therapies. We used a pooled shRNA library that covered 5043 different genes and combined transfection with exposure to either azacytidine or cytarabine analog to the concept of synthetic lethality. Suppression of the chemokine CXCL12 ranked highly among the candidates of the cytarabine group. Azacytidine in combination with suppression of genes within the neddylation pathway led to synergistic results. NEDD8 and RBX1 inhibition by the small molecule inhibitor pevonedistat inhibited leukemia cell growth. These findings establish an in vitro synergism between NEDD8 inhibition and azacytidine in AML. Taken together, neddylation constitutes a suitable target pathway for azacytidine combination strategies.
Identifiants
pubmed: 34857808
doi: 10.1038/s41598-021-02695-0
pii: 10.1038/s41598-021-02695-0
pmc: PMC8639713
doi:
Substances chimiques
Chemokine CXCL12
0
Cyclopentanes
0
NEDD8 Protein
0
NEDD8 protein, human
0
Pre-B-Cell Leukemia Transcription Factor 1
0
Pyrimidines
0
PBX1 protein, human
0
Azacitidine
M801H13NRU
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23280Informations de copyright
© 2021. The Author(s).
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