Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

Abstract

Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.

People
Malik, Natasha
Author

Da Silva Costa, Ana and Ghouri, Iffath and Johnston, Alexander and Mcglynn, Karen and McNair, Andrew and Bowman, Peter and Malik, Natasha and Hurren, Johanne and Bingelis, Tomas and Dunne, Michael and Smith, Godfrey L. and Kemi, Ole J. (2023) Electrically stimulated in vitro heart cell mimic of acute exercise reveals novel immediate cellular responses to exercise: Reduced contractility and metabolism, but maintained calcium cycling and increased myofilament calcium sensitivity. Cell Biochemistry and Function, 41 (8). pp. 1147-1161. ISSN 0263-6484

Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Hay, Jodie
Author

Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723

Wei, Jia and Stoesser, Nicole and Matthews, Philippa C. and Khera, Tarnjit and Gethings, Owen and Diamond, Ian and Studley, Ruth and Taylor, Nick and Peto, Tim E. A. and Walker, A. Sarah and Pouwels, Koen B. and Eyre, David W. and Rourke, Emma and Thomas, Tina and Pienaar, Dawid and Preece, Joy and Crofts, Sarah and Lloyd, Lina and Bowen, Michelle and Ayoubkhani, Daniel and Black, Russell and Felton, Antonio and Crees, Megan and Jones, Joel and Sutherland, Esther and Crook, Derrick W. and Pritchard, Emma and Vihta, Karina-Doris and Howarth, Alison and Marsden, Brian D. and Chau, Kevin K. and Ferreira, Lucas Martins and Dejnirattisai, Wanwisa and Mongkolsapaya, Juthathip and Hoosdally, Sarah and Cornall, Richard and Stuart, David I. and Screaton, Gavin and Lythgoe, Katrina and Bonsall, David and Golubchik, Tanya and Fryer, Helen and Newton, John N. and Bell, John I. and Cox, Stuart and Paddon, Kevin and James, Tim and House, Thomas and Robotham, Julie and Birrell, Paul and Jordan, Helena and Sheppard, Tim and Athey, Graham and Moody, Dan and Curry, Leigh and Brereton, Pamela and Jarvis, Ian and Godsmark, Anna and Morris, George and Mallick, Bobby and Eeles, Phil and Hay, Jodie and VanSteenhouse, Harper and Lee, Jessica and White, Sean and Evans, Tim and Bloemberg, Lisa and Allison, Katie and Pandya, Anouska and Davis, Sophie and Conway, David I. and MacLeod, Margaret and Cunningham, Chris (2024) Risk of SARS-CoV-2 reinfection during multiple Omicron variant waves in the UK general population. Nature Communications, 15: 1008. ISSN 2041-1723

Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Almuhanna, Hassan N.B.
Author

Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Dunn, Karen M.
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723

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Lees, Jamie
Author

Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Cassels, Jennifer
Author

Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716

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Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Li, Jiatian
Author

Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Nakagawa, Rinako
Author

Malik, Natasha and Hay, Jodie and Almuhanna, Hassan N.B. and Dunn, Karen M. and Lees, Jamie and Cassels, Jennifer and Li, Jiatian and Nakagawa, Rinako and Sansom, Owen J. and Michie, Alison M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37. pp. 2414-2425. ISSN 0887-6924

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Sansom, Owen
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT Consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Author Correction: Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (6): 1321. ISSN 1061-4036

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Michie, Alison M.
Author

Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716

Patterson, Shaun D. and Massett, Matthew E. and Huang, Xu and Jørgensen, Heather G. and Michie, Alison M. (2024) The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Molecular Oncology, 18 (9). pp. 2234-2254. ISSN 1574-7891

Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723

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