Structural and functional consequences of the STAT5B N642H driver mutation

Nat Commun. 2019 Jun 7;10(1):2517. doi: 10.1038/s41467-019-10422-7.

Abstract

Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5BN642H, 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 STAT5BN642H in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5BN642H-driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5BN642H patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5BN642H crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5BN642H can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5BN642H, conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5BN642H activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Hematologic Neoplasms / genetics
  • Humans
  • Intraepithelial Lymphocytes*
  • Leukemia, T-Cell / genetics*
  • Lymphoma, T-Cell / genetics*
  • Mice
  • Mice, Transgenic
  • Molecular Docking Simulation
  • Mutation*
  • STAT5 Transcription Factor / genetics*
  • src Homology Domains

Substances

  • STAT5 Transcription Factor
  • STAT5B protein, human