TIAR-dependent coordination of alternative splicing and lipid peroxidation is required for CML cell resistance to imatinib in the bone marrow stroma

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for chronic myeloid leukemia (CML), yet fail to eliminate quiescent CML cells residing in the bone marrow (BM). While transcriptome adaptation and metabolic rewiring have been recognized as mechanisms enabling CML survival, the contribution of RNA processing, known to expand the repertoire of isoforms and directly mediate therapy resistance in leukemia, is poorly characterized. 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 developed a humanized BM stromal niche in vivo to investigate the influence of the human BM microenvironment on gene expression and AS in CML cells. Stroma-facilitated transcriptome adaptation targeted transcription regulation, transmembrane transport, lipid metabolism, respiration and energy production. We identified RNA-binding protein TIAR (T-cell intracellular antigen-related protein) as a key mediator of CML survival and determined that TIAR-dependent post-transcriptional regulation coordinates RNA processing-metabolism program induced by stromal interaction. Quantitative nascent proteome analysis confirmed that TIAR is a translational regulator of metabolic enzymes and proteins involved in imatinib-induced erythroid differentiation. In hypoxic co-culture with BM stromal cells, TIAR knockdown reduced the viable erythroid-differentiated cell population in association with increased lipid peroxidation and decreased redox potential. Taken together, these findings identify TIAR-dependent RNA processing within the BM niche as a previously unrecognized mechanism of CML therapy resistance and potential therapeutic vulnerability.