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

Area of Science:

• Epigenetics
• Cancer Biology
• Leukemia Research

Background:

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

Purpose of the Study:

• To investigate how PRC2 alterations impact signaling pathways in T-ALL.
• To determine if these pathway changes influence response to T-ALL therapies.
• To elucidate the mechanisms of asparaginase resistance in PRC2-deficient T-ALL.

Main Methods:

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

Main Results:

• PRC2 loss, specifically EZH2 deficiency, markedly reduced WNT-dependent stabilization of proteins (WNT/STOP) pathway activity.
• PRC2-deficient T-ALL cells showed significantly reduced sensitivity to asparaginase.
• 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 impairs WNT/STOP signaling, leading to asparaginase resistance in T-ALL.
• Targeting the proteasome offers a potential strategy to overcome induction treatment failure in PRC2-mutated T-ALL.
• Understanding PRC2's role in T-ALL epigenetics and therapy response is crucial for developing novel treatment approaches.