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...

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Autores principales:	Justine Klosner, Konstantin Agelopoulos, Christian Rohde, Stefanie Göllner, Christoph Schliemann, Wolfgang E. Berdel, Carsten Müller-Tidow
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a8b83f0e4ce942518edcffdec910ac51
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spelling	oai:doaj.org-article:a8b83f0e4ce942518edcffdec910ac512021-12-05T12:13:17ZIntegrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia10.1038/s41598-021-02695-02045-2322https://doaj.org/article/a8b83f0e4ce942518edcffdec910ac512021-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02695-0https://doaj.org/toc/2045-2322Abstract 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.Justine KlosnerKonstantin AgelopoulosChristian RohdeStefanie GöllnerChristoph SchliemannWolfgang E. BerdelCarsten Müller-TidowNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Justine Klosner Konstantin Agelopoulos Christian Rohde Stefanie Göllner Christoph Schliemann Wolfgang E. Berdel Carsten Müller-Tidow Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
description	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.
format	article
author	Justine Klosner Konstantin Agelopoulos Christian Rohde Stefanie Göllner Christoph Schliemann Wolfgang E. Berdel Carsten Müller-Tidow
author_facet	Justine Klosner Konstantin Agelopoulos Christian Rohde Stefanie Göllner Christoph Schliemann Wolfgang E. Berdel Carsten Müller-Tidow
author_sort	Justine Klosner
title	Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
title_short	Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
title_full	Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
title_fullStr	Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
title_full_unstemmed	Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
title_sort	integrated rnai screening identifies the neddylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a8b83f0e4ce942518edcffdec910ac51
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Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia

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