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

• HNRNPC, an essential RNA-binding protein and m6A reader, coordinates oncogenic transcription and cell metabolism in T-ALL.

• T-ALL patients present elevated FTO levels and global m6A changes, and FTO targeting enhances the efficacy of existing treatment options.

RNA homeostasis is dysregulated in cancer and impacts disease progression and therapy resistance. N6-methyladenosine (m6A), the most abundant epitranscriptomic modification in eukaryotic mRNA, plays a pivotal role in RNA biology, affecting transcript stability, translation, and splicing. Our study uncovers the extensive m6A changes in T-cell acute lymphoblastic leukemia (T-ALL) patient samples for the first time. It reveals m6A's regulatory role in the oncogenic MYC and cholesterol biosynthesis pathways. In addition, we discovered that T-ALL is highly dependent on the m6A reader heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC is transcriptionally controlled by MYC and is an essential regulator of m6A-modified transcripts. Consequently, transcriptional silencing of HNRNPC profoundly impairs oncogenic pathways and critically diminishes leukemia cell growth. Additionally, the levels of the m6A demethylase fat mass and obesity-associated (FTO) are significantly elevated in T-ALL cells compared to normal cells, and to other types of leukemia. Targeting FTO shows therapeutic potential in preclinical disease models and synergizes with clinically relevant therapeutics. Our findings underscore the integral role of RNA methylation in orchestrating cancer cell oncogene expression and metabolism and highlight promising novel therapeutic avenues for the treatment of T-cell leukemia.