Title (en)
SBNO2 is a critical mediator of STAT3-driven hematological malignancies
Language
English
Description (en)
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.
Keywords (en)
Notch Homolog 2; Nf-Kappa-B; Antiinflammatory Response; Mitochondrial Stat3; Gene-Expression; Cancer; Cells; Pathogenesis; Activation; Inflammation
DOI
10.1182/blood.2022018494
Author of the digital object
Tania Brandstoetter  (University of Veterinary Medicine Vienna)
Veronika Sexl  (University of Veterinary Medicine Vienna / Universität Innsbruck)
Barbara Maurer  (University of Veterinary Medicine Vienna)
Satu Mustjoki  (University of Helsinki)
Johannes Zuber  (Vienna Biocenter)
Gregor Hoermann  (Munich Leukemia Laboratory)
Florian Grebien  (University of Veterinary Medicine Vienna)
Thomas Eder  (University of Veterinary Medicine Vienna)
Thorsten Klampfl  (University of Veterinary Medicine Vienna)
Jani Huuhtanen  (University of Helsinki / Aalto University)
Johannes Schmoellerl  (Vienna Biocenter)
Reinhard Grausenburger  (University of Veterinary Medicine Vienna)
Sebastian Kollmann  (University of Veterinary Medicine Vienna)
Eszter Doma  (University of Veterinary Medicine Vienna)
Format
application/pdf
Size
3.2 MB
Licence Selected
CC BY-NC-ND 4.0 International
Type of publication
Article
Name of Publication (en)
Blood
Pages or Volume
15
Volume
141
Number
15
From Page
1831
To Page
1845
Publisher
American Society of Hematology
Publication Date
2023