Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia

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 antileuke...

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Bibliographic Details
Published in:Scientific reports 2021-12, Vol.11 (1), p.23280-10, Article 23280
Main Authors: Klosner, Justine, Agelopoulos, Konstantin, Rohde, Christian, Göllner, Stefanie, Schliemann, Christoph, Berdel, Wolfgang E., Müller-Tidow, Carsten
Format: Article
Language:English
Subjects:
631/67/1990/283/1897
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Acute myeloid leukemia
Azacitidine - therapeutic use
Azacytidine
Chemokine CXCL12 - metabolism
Chemokines
Combined Modality Therapy
CXCL12 protein
Cyclopentanes - pharmacology
Cyclopentanes - therapeutic use
Cytarabine
HL-60 Cells
Humanities and Social Sciences
Humans
Lethality
Leukemia
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - therapy
multidisciplinary
Myeloid leukemia
NEDD8 Protein - metabolism
Pre-B-Cell Leukemia Transcription Factor 1 - metabolism
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
RNA Interference
RNA-mediated interference
Science
Science (multidisciplinary)
Signal Transduction - genetics
Signal Transduction - physiology
Synergism
Transfection
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-02695-0