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

Structural and functional consequences of the STAT5BN642H driver mutation.

Author information

1
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON, L5L 1C6, Canada.
2
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada.
3
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
4
Ludwig Boltzmann Institute for Cancer Research, 1090, Vienna, Austria.
5
Department of Physics, University of Toronto, 60 St. George Street, Toronto, ON, M5S 1A7, Canada.
6
Dalriada Drug Discovery, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON, L5L 1C6, Canada.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
8
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
9
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
10
Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
11
Clinical Institute of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1090, Vienna, Austria.
12
Structural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON, M5G 1L7, Canada.
13
Department of Chemistry, York University, 327C Life Sciences Building, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
14
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. dhepag@crystal.harvard.edu.
15
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA. dhepag@crystal.harvard.edu.
16
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. richard.moriggl@vetmeduni.ac.at.
17
Ludwig Boltzmann Institute for Cancer Research, 1090, Vienna, Austria. richard.moriggl@vetmeduni.ac.at.
18
Medical University of Vienna, 1090, Vienna, Austria. richard.moriggl@vetmeduni.ac.at.
19
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON, L5L 1C6, Canada. patrick.gunning@utoronto.ca.
20
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada. patrick.gunning@utoronto.ca.

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.

PMID:
31175292
PMCID:
PMC6555848
DOI:
10.1038/s41467-019-10422-7
[Indexed for MEDLINE]
Free PMC Article

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