Structural and functional consequences of the STAT5B driver mutation.

Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5B, a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5B in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5B-driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5B patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5B crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5B can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5B, conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5B activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.