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 (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.