The role of vtRNA2-1 in PKR activation. A simplified theoretical model of PKR activation and its influence on downstream pathways with (A) hypomethylation of the promoter, (B) monoallelic methylation of the promoter, or (C) biallelic hypermethylation of the promoter. On stimulation by various stress stimuli, for example, DNA damage induced by chemotherapy, PKR becomes autophosphorylated to an active kinase (pPKR) that activates multiple signaling pathways. (A) In AML blasts with a hypomethylated VTRNA2-1 promoter, vtRNA2-1 inhibits pPKR and favors the apoptotic pathways. (B) In AML blast with monoallelic methylation, pPKR increases because of the decrease in vtRNA2-1 and balance the different downstream signaling pathways. (C) When vtRNA2-1 expression is lost, the inhibitory effect disappears, pPKR increases and favor the activation of survival pathways (using data from Lee et al,¹⁷  Blalock et al,¹⁹  Blalock et al,⁴³  and Pataer et al⁴⁴ ).