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

Maryam Ghashghaei, 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 and Ly P. Vu ()
Additional contact information
Maryam Ghashghaei: University of British Columbia
Yilin Liu: British Columbia Cancer Research Centre Vancouver
James Ettles: CRUK Beatson Institute
Giuseppe Bombaci: Indiana University Simon Comprehensive Cancer Center
Niveditha Ramkumar: British Columbia Cancer Research Centre Vancouver
Zongmin Liu: University of British Columbia
Leo Escano: British Columbia Cancer Research Centre Vancouver
Sandra Spencer Miko: British Columbia Cancer Research Centre
Yerin Kim: British Columbia Cancer Research Centre Vancouver
Joseph A. Waldron: CRUK Beatson Institute
Kim Do: Memorial Sloan Kettering Cancer Center
Kyle MacPherson: British Columbia Cancer Research Centre Vancouver
Katie A. Yuen: British Columbia Cancer Research Centre Vancouver
Thilelli Taibi: British Columbia Cancer Research Centre Vancouver
Marty Yue: British Columbia Cancer Research Centre Vancouver
Aaremish Arsalan: British Columbia Cancer Research Centre Vancouver
Zhen Jin: University of British Columbia
Glenn Edin: British Columbia Cancer Research Centre Vancouver
Aly Karsan: British Columbia Cancer Research Centre
Gregg B. Morin: British Columbia Cancer Research Centre
Florian Kuchenbauer: British Columbia Cancer Research Centre Vancouver
Fabiana Perna: Indiana University Simon Comprehensive Cancer Center
Martin Bushell: CRUK Beatson Institute
Ly P. Vu: University of British Columbia

Nature Communications, 2024, vol. 15, issue 1, 1-18

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.

Date: 2024
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DOI: 10.1038/s41467-024-46665-2

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