| First Author | de Araujo ED | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 2517 |
| PubMed ID | 31175292 | Mgi Jnum | J:283551 |
| Mgi Id | MGI:6323918 | Doi | 10.1038/s41467-019-10422-7 |
| Citation | de Araujo ED, et al. (2019) Structural and functional consequences of the STAT5B(N642H) driver mutation. Nat Commun 10(1):2517 |
| abstractText | Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5B(N642H), 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(N642H) in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5B(N642H)-driven transformation of gammadelta T-cells in in vivo syngeneic transplant models, comparable to STAT5B(N642H) patient gammadelta T-cell entities. Importantly, we present human STAT5B and STAT5B(N642H) crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5B(N642H) can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5B(N642H), conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5B(N642H) activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B. |
