Revealing the transformative role of METTL13 in human hematopoietic stem cells and progression of pediatric leukemia

Childhood leukemia's five year survival rate has been improving over the last 40 years, but still only reaches 86.3% relative survival in the United States according to the Surveillance, Epidemiology, and End Results (SEER) program in 2025. Aberrant post-transcriptional RNA modifications, specifically N6-methyladenosine (m6A) methylation and adenosine to inosine (A-to-I) editing have previously been shown to push malignant transformations of hematopoietic stem cells (HSC). In order to unravel the mechanism behind these RNA modifiers and decipher whether methyltransferases (METTLs, such as METTL3 and METTL14) catalyzing m6A methylation work in concert with the A-to-I editing enzymes, adenosine deaminase acting on RNA 1 (ADAR1) to drive malignant transformation of HSCs. By first exploring differentially expressed genes in lentiviral over-expressed ADAR1 hematopoietic cells and progenitor cells we observed downregulation in the m6A complex (i.e. METTL3, METTL14, and other METTLs), except METTL13. While METTL13 knockdown converged with the other m6A complex knockdown results in immune signaling and survival, METTL13 knockdown uniquely affected cancer related pathways compared to other METTLs. Using publicly available RNA sequencing data from TARGET, we determined that increased METTL13 expression, in both T cell ALL and B cell ALL correlated to poor patient prognosis. Additionally, functional studies for cell proliferation and survival, both in vitro and in vivo, demonstrated METTL13's role in T-ALL when it is removed or lost. Overall these findings display the oncogenic role of METTL13 in T-ALL pathogenesis and pre-leukemic transformations, while revealing a continued research into this potential novel target for new therapies.