Wnt/STOP activation drives temporally dynamic ribosomal biogenesis in drug resistant leukemia cells

Studies have demonstrated that resistant leukemia cells depend on GSK3α-mediated proteasomal degradation as an alternative source of amino acids to survive treatment with asparaginase. Inhibition of this degradation machinery, termed Wnt-dependent stabilization of proteins (Wnt/STOP), limits generation of free amino acids, creating a therapeutic vulnerability. However, the underlying signaling processes bridging the activation of Wnt/STOP and cell death remain elusive. Here, we show that unexpectedly Wnt/STOP mediated apoptosis is independent of known stress signaling pathways such as the unfolded protein response or the kinase GCN2 whose main characteristic is the sensing of amino acid depletion within the integrated stress response. Additionally, we could find independence from changes in cell cycle progression and expression of the asparagine synthesizing enzyme ASNS. Instead, leveraging RNA-sequencing we could identify a temporally dynamic role for ribosomal proteins in mediating Wnt/STOP induced apoptosis. Collectively, our findings indicate ribosomal biogenesis as a previously unrecognized key factor in Wnt/STOP mediated asparaginase sensitization.

Publication History

Article published online:
12 May 2023