METTL13 Promotes Pre-Leukemic Transformation and the Development of Pediatric Leukemia

Abstract

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. SignificanceIn this study we uncovered a novel regulatory link between ADAR1 and the METTL-family of RNA methyltransferases in hematopoietic stem cells. Overexpression of ADAR1 uniquely upregulated METTL13 while suppressing other METTL genes. Loss of orphan gene METTL13 affected proliferation, apoptosis and p53 signaling in hematopoietic stem cells. Furthermore, loss of METTL13 suppressed cell proliferation and survival in pediatric T-cell acute lymphoblastic leukemia. Our findings suggest a potential role for METTL13 in pre-leukemia transformation and oncogenic development.