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 propo... More
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.
