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Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
,
Yasmin Jenkins,
Victoria D. Assmann,
Silpita Paul,
Nitesh D. Sharma,
Catherine Moore,
Eric H. Ma,
Paraskevi Diamanti,
Marc Hennequart,
Julianna Blagih,
Le Le,
Benjamin Jenkins,
Sophie Rouvray,
James Cronin ,
Russell G. Jones,
Marc Mansour,
Allison Blair,
Christina Halsey,
Ksenia Matlawska-Wasowska,
Daniel Herranz,
Emma E. Vincent,
Nick Jones
Molecular Metabolism, Volume: 102, Start page: 102275
Swansea University Authors:
Fernando Ponce Garcia , Yasmin Jenkins, Catherine Moore, Benjamin Jenkins, Sophie Rouvray, James Cronin , Nick Jones
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DOI (Published version): 10.1016/j.molmet.2025.102275
Abstract
T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondri...
| Published in: | Molecular Metabolism |
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| ISSN: | 2212-8778 |
| Published: |
Elsevier BV
2025
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70760 |
| Abstract: |
T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL. |
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| Keywords: |
eukaemia; Serine; Glycine; Metabolism; T-ALL; Canagliflozin |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This research was funded by The Little Princess Trust in partnership with Children's Cancer and Leukaemia Group (CCLG) awarded to NJ (CCLGA 2021 05) and a Research Wales Innovation Fund (RWIF) Collaboration Booster Fund Project funded by HEFCW. N.J. is supported by an MRC New Investigator Research Grant (MR/X000095/1). E.E.V is supported by an MRC Research Grant (MR/Z505651/1) and by Cancer Research UK (C18281/A29019). KM-W was supported by grants from the National Cancer Institute (NCI) at the National Institutes of Health, including R01 CA237165 and R01 CA282701. DH was supported by The Leukemia & Lymphoma Society Scholar Award 1386-23. YRJ is funded by a Swansea University Research Excellence Scholarship. VDA was supported by a Scotland Centre Cancer Research UK Non-Clinical Training Award (CANCTA-2022/100006) and CH by a Cancer Research UK Programme Foundation Award (DRCPFA-Nov21∖100001). |
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102275 |