Structural and functional consequences of the STAT5BN642H driver mutation

Elvin D. de Araujo, Fettah Erdogan, Heidi A. Neubauer, Deniz Meneksedag-Erol, Pimyupa Manaswiyoungkul, Mohammad S. Eram, Hyuk-Soo Seo, Abdul K. Qadree, Johan Israelian, Anna Orlova, Tobias Suske, Ha T. T. Pham, Auke Boersma, Simone Tangermann, Lukas Kenner, Thomas Rülicke, Aiping Dong, Manimekalai Ravichandran, Peter J. Brown, Gerald F. Audette, Sarah Rauscher, Sirano Dhe-Paganon (), Richard Moriggl () and Patrick T. Gunning ()
Additional contact information
Elvin D. de Araujo: University of Toronto Mississauga
Fettah Erdogan: University of Toronto Mississauga
Heidi A. Neubauer: University of Veterinary Medicine Vienna
Deniz Meneksedag-Erol: University of Toronto Mississauga
Pimyupa Manaswiyoungkul: University of Toronto Mississauga
Mohammad S. Eram: University of Toronto Mississauga
Hyuk-Soo Seo: Dana-Farber Cancer Institute
Abdul K. Qadree: University of Toronto Mississauga
Johan Israelian: University of Toronto Mississauga
Anna Orlova: University of Veterinary Medicine Vienna
Tobias Suske: University of Veterinary Medicine Vienna
Ha T. T. Pham: University of Veterinary Medicine Vienna
Auke Boersma: University of Veterinary Medicine Vienna
Simone Tangermann: University of Veterinary Medicine Vienna
Lukas Kenner: Ludwig Boltzmann Institute for Cancer Research
Thomas Rülicke: University of Veterinary Medicine Vienna
Aiping Dong: University of Toronto
Manimekalai Ravichandran: University of Toronto
Peter J. Brown: University of Toronto
Gerald F. Audette: York University
Sarah Rauscher: University of Toronto Mississauga
Sirano Dhe-Paganon: Dana-Farber Cancer Institute
Richard Moriggl: University of Veterinary Medicine Vienna
Patrick T. Gunning: University of Toronto Mississauga

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-10422-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10422-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-10422-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().