Phase Separated RBM15-NICD Condensates Orchestrate m6A-Epitranscriptomic Amplification of Notch-Driven Oncogenesis
T-cell acute lymphoblastic leukemia (T-ALL) represents a major cause of cancer-related mortality in children, driven primarily by aberrant hyperactivation ofhyperactivated Notch signaling. While NOTCH1 mutations are prevalent in T-ALL, effective therapeutic targeting remains challenging due to toxicity and acquired resistance mechanisms. Here, we reveal a previously unrecognized mechanism of T-ALL pathogenesis linking epitranscriptomic regulation to oncogenic transcription through biomolecular condensates. We demonstrate that RBM15 (nito in Drosophila), a key adaptor for the m6A methyltransferase complex, undergoes liquid-liquid phase separation (LLPS) with the Notch intracellular domain (NICD) to form dynamic condensates. These structures function as integrated regulatory hubs that simultaneously enhance transcription of Notch target genes and stabilize their mRNAs via m6A modification, creating a feedforward amplification loop essential for tumorigenesis. Using Drosophila tumor models and human T-ALL systems, we show that condensate formation depends on the RBM15 SPOC domain and correlates with elevated m6A levels in malignant cells. Importantly, we identify the FDA-approved glucocorticoidcorticosteroid deflazacort as a selective disruptor of these oncogenic condensates, which synergizes with existing therapies to potently suppress tumor growth in preclinical models. Our findings establish phase-separated RBM15-NICD condensates as an evolutionary conserved mechanism controlling cancer cell fate and reveal condensate disruption as a promising therapeutic paradigm for T-ALL treatment and precision oncology.