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

ABSTRACT: 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.

SUBMITTER: Klosner J

PROVIDER: S-EPMC8639713 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Klosner Justine J Agelopoulos Konstantin K Rohde Christian C Göllner Stefanie S Schliemann Christoph C Berdel Wolfgang E WE Müller-Tidow Carsten C

Scientific reports 20211202 1

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 ...[more]

PMID: 34857808

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Project description:Simple Summary Leukemic growth results in selective silencing of gene transcripts involved in immune detection, differentiation, and apoptosis. Hypomethylating agents (HMAs), such as 5-azacytidine, have been shown to reprogram the genetic landscape in various cancers to restore both transgene and endogenous transcript expression. In this study, we show that 5-azacytidine treatment re-establishes both luciferase (transgene) and immune-related (endogenous) transcript expression in murine leukemia models, highlighting the broad applicability of HMAs in rescuing tumor suppressor and tumor antigen gene expression and enhancing cancer susceptibility to immunity. In addition, the immune microenvironment undergoes alterations after 5-azacytidine treatment, giving additional insight into the varied mechanisms behind 5-azacytidine-induced tumor growth control and possible combinatorial approaches to better control leukemia. Abstract Cancer cells accumulate epigenetic modifications that allow escape from intrinsic and extrinsic surveillance mechanisms. In the case of acute myeloid leukemias (AML) and myelodysplastic syndromes, agents that disrupt chromatin structure, namely hypomethylating agents (HMAs), have shown tremendous promise as an alternate, milder treatment option for older, clinically non-fit patients. HMAs reprogram the epigenetic landscape in tumor cells through the reversal of DNA hypermethylation. Therapeutic effects resulting from these epigenetic changes are incredibly effective, sometimes resulting in complete remissions, but are frequently lost due to primary or acquired resistance. In this study, we describe syngeneic murine leukemias that are responsive to the HMA 5-azacytidine (5-Aza), as determined by augmented expression of a transduced luciferase reporter. We also found that 5-Aza treatment re-established immune-related transcript expression, suppressed leukemic burden and extended survival in leukemia-challenged mice. The effects of 5-Aza treatment were short-lived, and analysis of the immune microenvironment reveals possible mechanisms of resistance, such as simultaneous increase in immune checkpoint protein expression. This represents a model system that is highly responsive to HMAs and recapitulates major therapeutic outcomes observed in human leukemia (relapse) and may serve as a pre-clinical tool for studying acquired resistance and novel treatment combinations.

Dataset Information

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

Publications

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

Similar Datasets

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