Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity

Loss-of-function mutations and deletions in the core components of the epigenetic polycomb repressive complex 2 (PRC2) are associated with poor initial treatment response in T-cell 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. The 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 the samples of patients with T-ALL 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, which bolstered the asparagine reserves of leukemia cells. These results also strongly correlated with transcriptional profiles of asparaginase resistance in an independent cohort of patients with T-ALL. 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.