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

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Loss-of-function mutations in Polycomb Repressive Complex 2 (PRC2) are linked to poor treatment response in T-cell acute lymphoblastic leukemia (T-ALL).
• Mechanisms underlying T-ALL therapy resistance due to PRC2 alterations remain unclear.

Purpose of the Study:

• Investigate how PRC2 alterations impact signaling pathways in T-ALL.
• Determine if these pathway changes influence response to leukemia therapies.

Main Methods:

• Utilized an isogenic T-ALL cellular model and primary patient data.
• Integrated transcriptomic, proteomic, and phosphoproteomic analyses.
• Correlated findings with patient transcriptional profiles.

Main Results:

• PRC2 deficiency, specifically EZH2 loss, markedly reduced WNT-dependent stabilization of proteins (WNT/STOP) pathway activity.
• PRC2 loss significantly decreased sensitivity to asparaginase, a key T-ALL treatment.
• This resistance was linked to increased cellular ubiquitination and bolstered asparagine reserves due to WNT/STOP suppression.
• Asparaginase resistance in PRC2-depleted T-ALL correlated with patient data and could be mitigated by proteasome inhibition.

Conclusions:

• PRC2 loss confers asparaginase resistance in T-ALL via WNT/STOP pathway suppression and altered cellular metabolism.
• Pharmaceutical proteasome inhibition presents a potential strategy to overcome asparaginase resistance in PRC2-mutated T-ALL.
• Understanding these mechanisms offers a potential avenue to improve induction treatment outcomes.