The Role of RNA Epigenetic Modification in Normal and Malignant Hematopoiesis

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 N(6)-methyladenosine (m(6)A), in hematopoietic stem cells under normal conditions and in malignancy. RECENT FINDINGS: The m(6)A RNA modification is a critical regulator of hematopoiesis. Disruption of different elements of the m(6)A machinery can skew the balance of self-renewal and differentiation in normal hematopoietic stem cells. The m(6)A reader, writer, and eraser proteins are also overexpressed in myeloid leukemia, and disruption of their function impairs leukemogenesis. RNA m(6)A 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 m(6)A, inducing deleterious inflammatory pathways which compromise stem cell function. SUMMARY: The RNA modification m(6)A exerts a variety of functions in normal hematopoietic stem cells as well as leukemic cells. Pharmacologic modulation of different elements of the m(6)A machinery provides a promising avenue for ex vivo expansion of hematopoietic stem cells in the transplant setting, as well as for leukemia therapy.