Lefeivre, Thomas;
Grosu, Theodora-Ioana;
Tudose, Cosmin;
Jones, Luke;
Leon, Theresa Elizabeth;
Wynne, Kieran;
Oliviero, Giorgio;
... Bond, Jonathan; + view all
(2025)
Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity.
Blood Advances
10.1182/bloodadvances.2024015408.
(In press).
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Abstract
Loss-of-function mutations and deletions in core components of the epigenetic Polycomb Repressive Complex 2 (PRC2) are associated with poor initial treatment response in T-acute lymphoblastic leukemia (T-ALL), but the mechanisms that underpin resistance to individual therapies are unknown. We leveraged an isogenic T-ALL cellular model and primary patient data to investigate how PRC2 alterations affect signaling pathway activity in leukemia cells, and whether these changes may influence therapy response. Integration of transcriptomic, proteomic and phosphoproteomic results revealed markedly reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in leukemia cells lacking core PRC2 factor EZH2. Importantly, these results closely matched transcriptional readouts from T-ALL patient samples with PRC2 mutations and deletions. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels due to WNT/STOP suppression that bolstered leukemia cell asparagine reserves. These results also strongly correlated with transcriptional profiles of asparaginase resistance in an independent T-ALL patient cohort. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a potential avenue to tackle induction treatment failure in these cases.
| Type: | Article |
|---|---|
| Title: | Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/bloodadvances.2024015408 |
| Publisher version: | https://doi.org/10.1182/bloodadvances.2024015408 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10218956 |
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