The Role of RNA Epigenetic Modification in Normal and Malignant Hematopoiesis

Abstract

Purpose of Review: RNA epigenetic modifications have been identified as novel, dynamic regulators of gene expression, with important impacts on stem cell fate decisions. Here, we examine the functions of RNA modifications, with a focus on N6-methyladenosine (m6A), in hematopoietic stem cells under normal conditions and in malignancy. Recent Findings: The m6A RNA modification is a critical regulator of hematopoiesis. Disruption of different elements of the m6A machinery can skew the balance of self-renewal and differentiation in normal hematopoietic stem cells. The m6A reader, writer, and eraser proteins are also overexpressed in myeloid leukemia, and disruption of their function impairs leukemogenesis. RNA m6A modification governs important aspects of immune system function, including immune cell development, immune signaling, and recognition of RNA as foreign or self. In hematopoietic stem cells, endogenously derived double-stranded RNA can form in the absence of m6A, inducing deleterious inflammatory pathways which compromise stem cell function. Summary: The RNA modification m6A exerts a variety of functions in normal hematopoietic stem cells as well as leukemic cells. Pharmacologic modulation of different elements of the m6A machinery provides a promising avenue for ex vivo expansion of hematopoietic stem cells in the transplant setting, as well as for leukemia therapy.