Allison Siegenfeld, MS, PhD

The RNA modification m6A is perturbed in cancer and influences virtually all stages of the RNA lifecycle. In this proposal we use acute inhibitors of the m6A methyltransferase METTL3 to study how m6A directly affects RNA biogenesis in Acute Myeloid Leukemia (AML). Despite reports that long-term METTL3 loss impacts transcription, we find that acute METTL3 inhibition causes minimal changes in RNA synthesis. Instead, gene upregulation reflects increased RNA stability. Although regulation of RNA stability by cytoplasmic m6A readers is well-established, these data suggest an alternative mechanism. Specifically, we observe altered 3’ Untranslated Region (UTR) selection at upregulated genes. 3’ UTRs are known to impact mRNA abundance, suggesting that co-transcriptional 3’ end selection is central to m6A function and may underly effects previously ascribed to downstream mechanisms. We will therefore evaluate how m6A directly influences AML cell survival through regulation of 3’ end processing.