Uncovering a role for METTL13 in malignant transformation of human hematopoietic stem cells and in the progression of pediatric leukemia.

Post-transcriptional RNA modifications, such as N6-methyladenosine (m6A) methylation and adenosine to inosine (A-to-I) editing, are critical regulators of hematopoietic stem cell (HSC) self-renewal and differentiation, yet their precise contributions to malignant transformation are not fully elucidated. In this study, we uncovered the epitranscriptomic landscape caused by knockdown of genes from the methyltransferase (METTL)-family in hematopoietic stem and progenitor cells (HSPCs). We identified both converging and distinct roles of METTL3 and METTL14, known members of the m6A writer complex, as well as orphan gene METTL13. Notably, METTL13 was uniquely upregulated by adenosine deaminase acting on RNA 1 (ADAR1) overexpression, while other METTL genes were downregulated. Knockdown of METTL13 altered the expression of multiple genes involved in oncogenic development in HSPCs. Furthermore, METTL13 was associated with a high-risk profile in pediatric T-cell acute lymphoblastic leukemia (T-ALL), and functional studies confirmed that METTL13 is required for T-ALL cell proliferation and survival both in vitro and in vivo. Collectively, our results indicate a previously unrecognized, oncogenic role for METTL13 in pre-leukemic transformation and T-ALL pathogenesis.