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 effects of METTL3 and METTL14, known members of the m6A writer complex, as well as orphan gene METTL13. Amongst METTL-family members, only METTL13 transcription was increased following adenosine deaminase acting on RNA 1 (ADAR1) overexpression in HSPCs. This transcriptional pattern suggests that METTL13 may participate in biological programs that partially overlap with those controlled by the m6A writer complex and ADAR1, although any mechanistic relationship remains undefined. Knockdown of METTL13 altered the expression of multiple genes involved in oncogenic development in HSPCs. Furthermore, METTL13 expression 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 identify METTL13 as a previously unrecognized regulator of leukemic transformation, independent of any presumed mechanistic interaction between RNA editing and m6A pathways.