SBNO2 is a critical mediator of STAT3-driven hematological malignancies

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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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BLOOD, Volume 141, issue 15
Gain-of-function mutations in the signal transducer and activator of transcription 3 (STAT3) gene are recurrently identified in patients with large granular lymphocytic leukemia (LGLL) and in some cases of natural killer (NK)/T-cell and adult T-cell leukemia/lymphoma. To understand the consequences and molecular mechanisms contributing to disease development and oncogenic transformation, we developed murine hematopoietic stem and progenitor cell models that express mutated STAT3Y640F. These cells show accelerated proliferation and enhanced self-renewal potential. We integrated gene expression analyses and chromatin occupancy profiling of STAT3Y640F-transformed cells with data from patients with T-LGLL. This approach uncovered a conserved set of direct transcriptional targets of STAT3Y640F. Among these, strawberry notch homolog 2 (SBNO2) represents an essential transcriptional target, which was identified by a comparative genome-wide CRISPR/Cas9-based loss-of-function screen. The STAT3-SBNO2 axis is also present in NK-cell leukemia, T-cell non-Hodgkin lymphoma, and NPM-ALK-rearranged T-cell anaplastic large cell lymphoma (T-ALCL), which are driven by STAT3-hyperactivation/mutation. In patients with NPM-ALK+ T-ALCL, high SBNO2 expression correlates with shorter relapse-free and overall survival. Our findings identify SBNO2 as a potential therapeutic intervention site for STAT3-driven hematopoietic malignancies.
Funding Information: The authors thank Sabine Fajmann, Petra Kudweis, Philipp Jodl, and Isabella Mayer for excellent experimental support. The authors thank the Biomedical Sequencing Facility at the CeMM Research Center for Molecular Medicine at the Austrian Academy of Sciences and the next-generation sequencing facility at Vienna BioCenter Core Facilities, a member of the Vienna BioCenter, Vienna, Austria. The authors also thank Stephan Hutter and Wecke Walter for bioinformatics support in the analysis of primary patient samples. This work was supported by the Austrian Science Fund (FWF) Special Research Program SFB-F6107 and the European Research Council under the European Union's Horizon 2020 research and innovation program grant agreements (#694354) (V.S.), (#636855) (F.G.), and (#647355) (S.M.). S.M. was supported by the Academy of Finland Heal-Art consortium (314442) and special COVID-19 funding (335527), ERA PerMed (JAKSTAT-TARGET consortium), Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Helsinki Institute for Life Science, and Cancer Foundation Finland. B.M. was supported by the Fellinger Cancer Research Association. Contribution: V.S. T.B. B.M. and J.S. conceptualized the study; T.B. performed most of the experiments; T.B. and J.S. analyzed all wet laboratory experiments; R.G. T.K. T.E. and J.H. analyzed sequencing data; J.S. E.D. and S.K. performed experiments; G.H. and S.M. provided bioinformatic patient data analysis; J.Z. S.M. G.H. and F.G. were involved in experimental design and scientific discussions; T.B. and V.S. wrote the manuscript; V.S. supervised the study; and all authors revised the manuscript.
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Brandstoetter, T, Schmoellerl, J, Grausenburger, R, Kollmann, S, Doma, E, Huuhtanen, J, Klampfl, T, Eder, T, Grebien, F, Hoermann, G, Zuber, J, Mustjoki, S, Maurer, B & Sexl, V 2023, ' SBNO2 is a critical mediator of STAT3-driven hematological malignancies ', Blood, vol. 141, no. 15, pp. 1831-1845 .