HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia

RNA homeostasis is critical for cancer progression and therapy resistance. N6-methyladenosine (m6A), the most abundant epitranscriptomic modification in eukaryotic mRNA, has recently been found to be critical for various aspects of RNA biology, such as transcript stability, translation, and splicing. Our study showcases extensive m6A changes in T-cell acute lymphoblastic leukemia, affecting oncogenic MYC targets and cholesterol biosynthesis. We also demonstrate that leukemia cells strongly depend on the m6A reader HNRNPC, which we found to be a key regulator of these MYC targets and cholesterol biosynthesis. Consequently, HNRNPC silencing profoundly impaired these m6A-regulated pathways, resulting in significantly reduced leukemia growth. Corroborating results were collected by inhibiting the m6A demethylase FTO, which was demonstrated to be therapeutically relevant in preclinical disease models, while also synergizing with chemotherapeutics. Collectively, we reveal a novel role of m6A in coordinating the crosstalk between oncogenic expression and metabolism and provide therapeutic avenues against T-cell leukemia. We investigated the effects of genetic and pharmacological modulation of the m6A pathway in T-cell acute lymphoblastic leukemia. RNAseq and m6A-eCLIP experiments were performed upon inhibition of pathway writers (METTL3) and erasers (FTO). In addition eCLIP experiments were performed for a relevant pathway reader (HNRNPC). Gene expression was evaluated in all experimental conditions.