N6-methyladenosine and its epitranscriptomic effects on hematopoietic stem cell regulation and leukemogenesis.

Abstract

N6-methyladenosine (m6A) RNA modification orchestrates cellular epitranscriptome through tuning the homeostasis of transcript stability, translation efficiency, and the transcript affinity toward RNA-binding proteins (RBPs). An aberrant m6A deposition on RNA can lead toward oncogenic expression profile (mRNA), impaired mitochondrial metabolism (mtRNA), and translational suppression (rRNA) of tumor suppressor genes. In addition, non-coding RNAs (ncRNAs), such as X-inactive specific transcript (XIST), miRNAs, and α-ketoglutarate-centric metabolic transcripts are also regulated by the m6A epitranscriptome. Notably, recent studies had uncovered a myriad of m6A-modified transcripts the center of hematopoietic stem cell (HSC) regulation, in which m6A modification act as a context dependent switch to the on and off of hematopoietic stem cell (HSC) maintenance, lineage commitment and terminal differentiation. In this review, we sequentially unfold the m6A mediated epithelial-to-hematopoietic transition in progenitor blood cell production, lymphocytic lineage expansion (T cells, B cells, NK cells, and non-NK ILCs), and the m6A crosstalk with the onco-metabolic prospects of leukemogenesis. Together, an encompassing body of evidence highlighted the emerging m6A significance in the regulation of HSC biology and leukemogenesis.