Cancer is an RNA disease: DNA is not destiny, RNA determines leukemia fate

The increasing incidence of myeloid cancers with age is commonly attributed to the accumulation of somatic pathologic variants throughout life. For example, the frequency of clonal hematopoiesis wherein variant hematopoietic stem cell clones increases with age [ 1 ]. However, several questions remain unresolved. Not all variants underlying CH result in haematological abnormalities or progress to leukaemia. Also, the same variant can be associated with different cancer phenotypes and trajectories. Further, there is a distinct peak in leukemia incidence during infancy despite the limited time to acquire somatic pathogenic variants. These data suggest somatic variants alone do not fully explain leukemia development. Prior data indicate that haematopoietic stem cell behavior and intrinsic and extrinsic factors shape disease evolution [ 2 ]. However, the molecular process(es) linking aging to selective clonal outgrowth is uncertain. We propose RNA dysregulation may be the missing layer. Somatic variants may identify risk, whilst changes at the RNA level may influence trajectory and determine leukemia fate.