Malik, N. , Hay, J. , Almuhanna, H. N.B., Dunn, K. M., Lees, J., Cassels, J., Li, J., Nakagawa, R., Sansom, O. J. and Michie, A. M. (2023) mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia. Leukemia, 37, pp. 2414-2425. (doi: 10.1038/s41375-023-02043-3) (PMID:37775560) (PMCID:PMC10681897)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Hay, Dr Jodie and Dunn, Mrs Karen and Lees, Mr Jamie and Malik, Miss Natasha and LI, Jiatian and Nakagawa, Dr Rinako and Michie, Professor Alison and Almuhanna, Hassan Nasser B and Sansom, Professor Owen and Cassels, Miss Jennifer |
| Creator Roles: | Michie, A.Conceptualization, Methodology, Investigation, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing Sansom, O.Conceptualization, Funding acquisition, Supervision, Writing – review and editing Malik, N.Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review and editing Hay, J.Conceptualization, Methodology, Investigation, Writing – review and editing Nakagawa, R.Methodology, Writing – review and editing Dunn, K.Methodology, Investigation, Writing – review and editing Almuhanna, H. N. B.Investigation, Writing – review and editing Lees, J.Investigation, Writing – review and editing Cassels, J.Investigation, Writing – review and editing |
| Authors: | Malik, N., Hay, J., Almuhanna, H. N.B., Dunn, K. M., Lees, J., Cassels, J., Li, J., Nakagawa, R., Sansom, O. J., and Michie, A. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Leukemia |
| Publisher: | Springer Nature |
| ISSN: | 0887-6924 |
| ISSN (Online): | 1476-5551 |
| Published Online: | 29 September 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Leukemia 37:2414–2425 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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