NPM-ALK–driven hematopoietic malignancies are addicted to SBNO2 expression, and SBNO2 expression is a prognostic marker in patients with NPM-ALK⁺ALCL. (A) SBNO2 expression across all cell lines within the cancer dependency map (DepMap).³⁷ Cell lines with high SBNO2 expression highlighted in red. (B) Reanalysis of DepMap data from 116 CRISPR-based LOF screens done using hematopoietic cell lines. Each dot represents a distinct screen. Gene effects were normalized to FDR-adjusted median effect size of defined core-essential and nonessential genes. (C) Competitive proliferation assays performed on human NPM-ALK⁺ T-ALCL cells transduced with shRNA vectors targeting either Renilla (negative control), MYC (positive control), STAT3, or SBNO2, respectively. Abundance of shRNA⁺ cells was normalized to day 4 after transduction (mean ± SD, n = 3). (D) Flow cytometric analysis (left) and quantification of annexin/7AAD-positve apoptotic cells (right) at the end point of competition assay shown in panel C have been shown. (E) Kaplan-Meier–based survival analysis of patients with NPM-ALK⁺ with high vs low SBNO2 expression upon reanalysis of publicly available data sets.⁴¹ Correlation of SBNO2 expression and relapse-free time was assessed through the log-rank test in panel E. (F) Schematic illustration of the proposed model. STAT3 hyperactivation induced through either oncogenic upstream signaling (eg, via NPM-ALK) or activating STAT3 mutations (eg, STAT3^Y640F) induce SBNO2 expression that is essential for cancer cell proliferation/survival.