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

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

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

RNA homeostasis is dysregulated in cancer and affects disease progression and therapy resistance. N6-methyladenosine (m⁶A), the most abundant epitranscriptomic modification in eukaryotic messenger RNA, plays a pivotal role in RNA biology, affecting transcript stability, translation, and splicing. Our study uncovers the extensive m⁶A changes in patients with T-cell acute lymphoblastic leukemia (T-ALL), to our knowledge, 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. In addition, the levels of the m⁶A demethylase fat mass and obesity-associated protein (FTO) are significantly elevated in T-ALL cells compared with 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.