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Type of publication: Journal Article
Type of document: Full Paper

Year: 2019

Authors: de Araujo, ED; Erdogan, F; Neubauer, HA; Meneksedag-Erol, D; Manaswiyoungkul, P; Eram, MS; Seo, HS; Qadree, AK; Israelian, J; Orlova, A; Suske, T; Pham, HTT; Boersma, A; Tangermann, S; Kenner, L; Rülicke, T; Dong, A; Ravichandran, M; Brown, PJ; Audette, GF; Rauscher, S; Dhe-Paganon, S; Moriggl, R; Gunning, PT

Title: Structural and functional consequences of the STAT5B

Source: Nat Commun. 2019; 10(1):2517



Authors Vetmeduni Vienna:

Boersma Auke
Kenner Lukas
Moriggl Richard
Neubauer Heidi
Orlova Anna
Pham Ha
Rülicke Thomas
Suske Tobias
Tangermann Simone

Vetmed Research Units
Institut für In-vivo und In-vitro-Modelle
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


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.

Keywords Pubmed: Animals
Hematologic Neoplasmsgenetics
Humans
Intraepithelial Lymphocytes
Leukemia, T-Cellgenetics
Lymphoma, T-Cellgenetics
Mice
Mice, Transgenic
Molecular Docking Simulation
Mutation
STAT5 Transcription Factorgenetics
src Homology Domains

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