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de Araujo, Elvin D.; Erdogan, Fettah; Neubauer, Heidi A.; Meneksedag-Erol, Deniz; Manaswiyoungkul, Pimyupa; Eram, Mohammad S.; Seo, Hyuk-Soo; Qadree, Abdul K.; Israelian, Johan; Orlova, Anna; Suske, Tobias; Pham, Ha T. T.; Boersma, Auke; Tangermann, Simone; Kenner, Lukas; Rülicke, Thomas; Dong, Aiping; Ravichandran, Manimekalai; Brown, Peter J.; Audette, Gerald F.; Rauscher, Sarah; Dhe-Paganon, Sirano; Moriggl, Richard; Gunning, Patrick T.
Nature communications, 06/2019, Volume: 10, Issue: 1Journal Article
Abstract 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 γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5B N642H patient γδ 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.
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