Structural and functional consequences of the STAT5B^N642H driver mutation

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Neubauer-Sedy, Heidi; Kenner, Lukas; Orlova, Anna; Suske, Tobias; Boersma, Auke

Abstrakt

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 yo T-cells in in vivo syngeneic transplant models, comparable to STAT5B(N642H) patient yo 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.

Dokumententyp

Originalarbeit

Open Access Type

Gold

DOI

10.1038/s41467-019-10422-7

PubMed ID

MEDLINE:31175292