TIAR-dependent coordination of alternative splicing and lipid peroxidation is required for CML cell resistance to...

Chronic myeloid leukemia (CML) is treated with Abl1 tyrosine kinase inhibitors (TKIs). Quiescent cancer cells residing in the bone marrow (BM) can survive the treatment and cause CML relapse. We previously found that a subset of alternative splicing (AS) changes detected in CML cells surviving months of therapy are initiated within hours of treatment onset. Here, we investigated how AS in CML cells is modulated by the human BM microenvironment. By incorporating humanized BM niche models in vivo, we uncovered stroma-induced transcriptome adaptation that influences transcriptional regulation, transmembrane transport, lipid metabolism, the tricarboxylic acid cycle, and respiratory electron transport. We identified RNA-binding protein TIAR (T-cell intracellular antigen-related protein) as a key mediator of CML survival under TKI imatinib treatment. Our data show TIAR-dependent coordination of RNA processing with the metabolic program induced by stromal interaction. Quantitative nascent proteome analysis revealed that TIAR silencing affects the synthesis of metabolic enzymes and proteins involved in imatinib-induced erythroid differentiation. Besides, TIAR knockdown increased lipid peroxidation in untreated cells and decreased reduction potential in cells upon imatinib treatment. Taken together, TIAR deficiency reduces CML survival, possibly by inducing ferroptosis. These findings identify TIAR-dependent RNA processing within the BM niche as a previously unrecognized mechanism of CML therapy resistance and a potential therapeutic vulnerability.