Fig. 1

Cancer can be promoted by upregulating either N ⁶-methyladenosine (m ⁶ A) demethylases or methyltransferase proteins. In breast cancer, hypoxia increases the expression of ALKBH5 or ZNF217 through the activation of hypoxia-inducible factors (HIFs). ALKBH5 is an m6A demethylating enzyme, and ZNF217 inhibits the RNA methylation writer complex (RBM15–WTAP–METTL3–METTL14), resulting in a reduction of the levels of the m⁶A modification in the mRNA of breast cancer pluripotency transcripts NANOG and KLF4, promoting their stability and increased expression. This contributes to the reacquisition of the breast cancer stem cell phenotype in these cells. In myeloid leukemia, by contrast, increased levels of components of the m⁶A methylation machinery proteins (RBM15–WTAP–METTL3–METTL14) are present, suggesting misregulated and increased mRNA methylation. Thus, the increase in these proteins might alter the normal differentiation trajectory of hematopoietic stem cells, leading to abnormal fates, including leukemic blasts. (Arrows indicate activation; ‘lightning bolts’ indicate misregulation of the RNA methylation program)