Rationale for targeted hyperactivation of oncogenic STAT5-signaling in acute lymphoblastic leukemia

These opposing phenotypes were driven by distinct transcriptional circuits: STAT5GOF induced MYC-dependent glycolysis and biomass accumulation, whereas STAT5LOF activated BCL6-dependent phosphatidylethanolamine (PtdEtn) synthesis, promoting autophagy and colony formation. To visualize Stat5aGOF/MYC and Stat5aLOF/BCL6 cell states, we engineered patient-derived xenografts with fluorescent MYC and BCL6 reporters. Single-cell imaging revealed autonomous transitions between MYC⁺ (STAT5-high) and BCL6⁺ (STAT5-low) states with a 4-hours periodicity.

Tyrosine kinase inhibitors (TKI) suppressed STAT5-activity in favor of quiescent BCL6⁺ cells. In contrast, the tyrosine phosphatase inhibitor (TPI) and immunotherapeutic osunprotafib3 hyperactivated STAT5, selectively killed B-ALL cells and subverted leukemia-initiation in vivo. Strikingly, osunprotafib potentiated treatment-responses to bispecific T-cell engagers (blinatumomab)4-5 and CD19 CAR T-cells6 and harnessed the combined effects of direct leukemia-specific toxicity and anti-leukemia T-cell activation.

While the TKI-paradigm exploits B-ALL addiction to oncogenic STAT5-activation, this study reveals a previously unrecognized dependency on robust STAT5-inhibition. Since osunprotafib achieved favorable safety profiles in cancer immunotherapy-trials7, targeted STAT5 hyperactivation could amplify treatment responses to blinatumomab and CD19 CAR T-cells for patients with refractory B-ALL.