Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis

Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of...
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Autor*in:	Maryam Ghashghaei [verfasserIn] Yilin Liu [verfasserIn] James Ettles [verfasserIn] Giuseppe Bombaci [verfasserIn] Niveditha Ramkumar [verfasserIn] Zongmin Liu [verfasserIn] Leo Escano [verfasserIn] Sandra Spencer Miko [verfasserIn] Yerin Kim [verfasserIn] Joseph A. Waldron [verfasserIn] Kim Do [verfasserIn] Kyle MacPherson [verfasserIn] Katie A. Yuen [verfasserIn] Thilelli Taibi [verfasserIn] Marty Yue [verfasserIn] Aaremish Arsalan [verfasserIn] Zhen Jin [verfasserIn] Glenn Edin [verfasserIn] Aly Karsan [verfasserIn] Gregg B. Morin [verfasserIn] Florian Kuchenbauer [verfasserIn] Fabiana Perna [verfasserIn] Martin Bushell [verfasserIn] Ly P. Vu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Übergeordnetes Werk:	In: Nature Communications - Nature Portfolio, 2016, 15(2024), 1, Seite 18
Übergeordnetes Werk:	volume:15 ; year:2024 ; number:1 ; pages:18

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41467-024-46665-2

Katalog-ID:	DOAJ095657983

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allfields	10.1038/s41467-024-46665-2 doi (DE-627)DOAJ095657983 (DE-599)DOAJ70b7701b4c0b40d88cc303cdcb9178b8 DE-627 ger DE-627 rakwb eng Maryam Ghashghaei verfasserin aut Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML. Science Q Yilin Liu verfasserin aut James Ettles verfasserin aut Giuseppe Bombaci verfasserin aut Niveditha Ramkumar verfasserin aut Zongmin Liu verfasserin aut Leo Escano verfasserin aut Sandra Spencer Miko verfasserin aut Yerin Kim verfasserin aut Joseph A. Waldron verfasserin aut Kim Do verfasserin aut Kyle MacPherson verfasserin aut Katie A. Yuen verfasserin aut Thilelli Taibi verfasserin aut Marty Yue verfasserin aut Aaremish Arsalan verfasserin aut Zhen Jin verfasserin aut Glenn Edin verfasserin aut Aly Karsan verfasserin aut Gregg B. Morin verfasserin aut Florian Kuchenbauer verfasserin aut Fabiana Perna verfasserin aut Martin Bushell verfasserin aut Ly P. Vu verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:18 https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/article/70b7701b4c0b40d88cc303cdcb9178b8 kostenfrei https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 18
spelling	10.1038/s41467-024-46665-2 doi (DE-627)DOAJ095657983 (DE-599)DOAJ70b7701b4c0b40d88cc303cdcb9178b8 DE-627 ger DE-627 rakwb eng Maryam Ghashghaei verfasserin aut Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML. Science Q Yilin Liu verfasserin aut James Ettles verfasserin aut Giuseppe Bombaci verfasserin aut Niveditha Ramkumar verfasserin aut Zongmin Liu verfasserin aut Leo Escano verfasserin aut Sandra Spencer Miko verfasserin aut Yerin Kim verfasserin aut Joseph A. Waldron verfasserin aut Kim Do verfasserin aut Kyle MacPherson verfasserin aut Katie A. Yuen verfasserin aut Thilelli Taibi verfasserin aut Marty Yue verfasserin aut Aaremish Arsalan verfasserin aut Zhen Jin verfasserin aut Glenn Edin verfasserin aut Aly Karsan verfasserin aut Gregg B. Morin verfasserin aut Florian Kuchenbauer verfasserin aut Fabiana Perna verfasserin aut Martin Bushell verfasserin aut Ly P. Vu verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:18 https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/article/70b7701b4c0b40d88cc303cdcb9178b8 kostenfrei https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 18
allfields_unstemmed	10.1038/s41467-024-46665-2 doi (DE-627)DOAJ095657983 (DE-599)DOAJ70b7701b4c0b40d88cc303cdcb9178b8 DE-627 ger DE-627 rakwb eng Maryam Ghashghaei verfasserin aut Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML. Science Q Yilin Liu verfasserin aut James Ettles verfasserin aut Giuseppe Bombaci verfasserin aut Niveditha Ramkumar verfasserin aut Zongmin Liu verfasserin aut Leo Escano verfasserin aut Sandra Spencer Miko verfasserin aut Yerin Kim verfasserin aut Joseph A. Waldron verfasserin aut Kim Do verfasserin aut Kyle MacPherson verfasserin aut Katie A. Yuen verfasserin aut Thilelli Taibi verfasserin aut Marty Yue verfasserin aut Aaremish Arsalan verfasserin aut Zhen Jin verfasserin aut Glenn Edin verfasserin aut Aly Karsan verfasserin aut Gregg B. Morin verfasserin aut Florian Kuchenbauer verfasserin aut Fabiana Perna verfasserin aut Martin Bushell verfasserin aut Ly P. Vu verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:18 https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/article/70b7701b4c0b40d88cc303cdcb9178b8 kostenfrei https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 18
allfieldsGer	10.1038/s41467-024-46665-2 doi (DE-627)DOAJ095657983 (DE-599)DOAJ70b7701b4c0b40d88cc303cdcb9178b8 DE-627 ger DE-627 rakwb eng Maryam Ghashghaei verfasserin aut Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML. Science Q Yilin Liu verfasserin aut James Ettles verfasserin aut Giuseppe Bombaci verfasserin aut Niveditha Ramkumar verfasserin aut Zongmin Liu verfasserin aut Leo Escano verfasserin aut Sandra Spencer Miko verfasserin aut Yerin Kim verfasserin aut Joseph A. Waldron verfasserin aut Kim Do verfasserin aut Kyle MacPherson verfasserin aut Katie A. Yuen verfasserin aut Thilelli Taibi verfasserin aut Marty Yue verfasserin aut Aaremish Arsalan verfasserin aut Zhen Jin verfasserin aut Glenn Edin verfasserin aut Aly Karsan verfasserin aut Gregg B. Morin verfasserin aut Florian Kuchenbauer verfasserin aut Fabiana Perna verfasserin aut Martin Bushell verfasserin aut Ly P. Vu verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:18 https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/article/70b7701b4c0b40d88cc303cdcb9178b8 kostenfrei https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 18
allfieldsSound	10.1038/s41467-024-46665-2 doi (DE-627)DOAJ095657983 (DE-599)DOAJ70b7701b4c0b40d88cc303cdcb9178b8 DE-627 ger DE-627 rakwb eng Maryam Ghashghaei verfasserin aut Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML. Science Q Yilin Liu verfasserin aut James Ettles verfasserin aut Giuseppe Bombaci verfasserin aut Niveditha Ramkumar verfasserin aut Zongmin Liu verfasserin aut Leo Escano verfasserin aut Sandra Spencer Miko verfasserin aut Yerin Kim verfasserin aut Joseph A. Waldron verfasserin aut Kim Do verfasserin aut Kyle MacPherson verfasserin aut Katie A. Yuen verfasserin aut Thilelli Taibi verfasserin aut Marty Yue verfasserin aut Aaremish Arsalan verfasserin aut Zhen Jin verfasserin aut Glenn Edin verfasserin aut Aly Karsan verfasserin aut Gregg B. Morin verfasserin aut Florian Kuchenbauer verfasserin aut Fabiana Perna verfasserin aut Martin Bushell verfasserin aut Ly P. Vu verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:18 https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/article/70b7701b4c0b40d88cc303cdcb9178b8 kostenfrei https://doi.org/10.1038/s41467-024-46665-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 18
language	English
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title	Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
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title_sort	translation efficiency driven by cnot3 subunit of the ccr4-not complex promotes leukemogenesis
title_auth	Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
abstract	Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.
abstractGer	Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.
abstract_unstemmed	Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.
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title_short	Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
url	https://doi.org/10.1038/s41467-024-46665-2 https://doaj.org/article/70b7701b4c0b40d88cc303cdcb9178b8 https://doaj.org/toc/2041-1723
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author2Str	Yilin Liu James Ettles Giuseppe Bombaci Niveditha Ramkumar Zongmin Liu Leo Escano Sandra Spencer Miko Yerin Kim Joseph A. Waldron Kim Do Kyle MacPherson Katie A. Yuen Thilelli Taibi Marty Yue Aaremish Arsalan Zhen Jin Glenn Edin Aly Karsan Gregg B. Morin Florian Kuchenbauer Fabiana Perna Martin Bushell Ly P. Vu
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doi_str	10.1038/s41467-024-46665-2
up_date	2024-07-03T15:49:45.172Z
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Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis

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