SBNO2 is a critical mediator of STAT3-driven hematological malignancies.

Gain-of-function mutations in the STAT3 gene are recurrently identified in patients suffering from large granular lymphocytic leukemia (LGLL) and some cases of T/NK 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 expressing mutated STAT3Y640F. The cells show accelerated proliferation and enhanced self-renewal potential. We integrated gene expression analyses and chromatin occupancy profiling of STAT3Y640F-transformed cells with T-LGLL patient data. This approach uncovered a conserved set of direct transcriptional targets of STAT3Y640F. Among those, the strawberry notch homolog 2 (SBNO2) represents an essential transcriptional target which was identified by a comparative genome-wide CRISPR/Cas9-based loss-of-function (LOF) screen. The STAT3-SBNO2 axis is also present in NK-cell leukemia, T-cell non Hodgkin-lymphoma (T-NHL) and NPM-ALK-rearranged T-anaplastic large cell lymphoma (T-ALCL), which are driven by STAT3-hyperactivation/mutation. In NPM-ALK T-ALCL patients, high SBNO2 expression correlates with shorter relapse-free- and overall survival. Our findings identify SBNO2 as potential therapeutic intervention site for STAT3-driven hematopoietic malignancies.