Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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.

People
Ghashghaei, Maryam
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Liu, Yilin
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Ettles, James
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Bombaci, Giuseppe
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Ramkumar, Niveditha
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Liu, Zongmin
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Escano, Leo
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Miko, Sandra Spencer
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Kim, Yerin
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Waldron, Joseph A.
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Do, Kim
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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MacPherson, Kyle
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Yuen, Katie A.
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Taibi, Thilelli
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Yue, Marty
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Arsalan, Aaremish
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Jin, Zhen
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Edin, Glenn
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Karsan, Aly
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Morin, Gregg B.
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Kuchenbauer, Florian
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Perna, Fabiana
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Bushell, Martin
Author

Dearlove, Emily L. and Chatrin, Chatrin and Buetow, Lori and Ahmed, Syed F. and Schmidt, Tobias and Bushell, Martin and Smith, Brian O. and Huang, Danny T. (2024) DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids. eLife, 13: RP98070. ISSN 2050-084X

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Vu, Ly P.
Author

Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P. (2024) Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature Communications, 15: 2340. ISSN 2041-1723

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Title:
Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
Creators:
Ghashghaei, Maryam and Liu, Yilin and Ettles, James and Bombaci, Giuseppe and Ramkumar, Niveditha and Liu, Zongmin and Escano, Leo and Miko, Sandra Spencer and Kim, Yerin and Waldron, Joseph A. and Do, Kim and MacPherson, Kyle and Yuen, Katie A. and Taibi, Thilelli and Yue, Marty and Arsalan, Aaremish and Jin, Zhen and Edin, Glenn and Karsan, Aly and Morin, Gregg B. and Kuchenbauer, Florian and Perna, Fabiana and Bushell, Martin and Vu, Ly P.
Identification Number:
10.1038/s41467-024-46665-2
Date:
15 March 2024
Divisions:
College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
Nature Research
Additional Information:
The work was supported by the Canadian Institutes for Health Research to L.P.V. (AWD-020547) and Natural Sciences and Engineering Research Council of Canada Discovery Grant. [...] L.P.V.’s lab is also supported by the Terry Fox Research Institute New Investigator Award. M.B., J.A.W., and J.E. were supported by Cancer Research UK core funding to the CRUK Beatson Institute (A31287) for M.B.’s lab (A29252) and to the CRUK Scotland Center (CTRQQR-2021\100006).
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https://pub.demo35.eprints-hosting.org/id/eprint/330
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Article
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Unnamed user with email ejo1f20@soton.ac.uk
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Date Deposited:
11 Jun 2025 16:37
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Last Modified:
12 Jun 2025 09:46
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