A small modification makes a big difference: rRNA modifications in hematopoiesis and leukemia

Hematopoietic stem cells (HSCs) sustain lifelong blood production through a fine balance between self-renewal and differentiation that demands a tight regulation of protein synthesis. HSCs are highly sensitive to translational perturbation, as exemplified by human ribosomopathies-a group of congenital bone marrow failure syndromes caused by mutations in ribosomal components and biogenesis factors. While the contribution of ribosome numbers to hematologic disease is established, ribosome composition is emerging as an equally important axis of regulation. A central source of this compositional diversity is ribosomal RNA (rRNA) nucleotide modifications-human rRNAs carry over 200 chemical modifications, primarily 2'-O-methylation and pseudouridylation, which were long regarded as static structural features but are now recognized as dynamically regulated during cellular differentiation. Perturbation of these modification patterns has profound consequences. In dyskeratosis congenita, germline mutations to rRNA modification-related proteins disrupt rRNA modifications landscape, and cause bone marrow failure through selective translational defects without globally compromising ribosomes numbers. Conversely, in acute myeloid leukemia, leukemic stem cells actively maintain high rRNA modification levels at specific sites to sustain self-renewal, metabolic fitness, and chemoresistance, effectively driving a stem-like translational state. In this review, we integrate findings from normal hematopoietic differentiation, congenital bone marrow failure syndromes, and leukemia to describe how rRNA modifications link translation to cell fate in the hematopoietic system. We discuss the dynamics of rRNA modifications as determinants of cellular identity and highlight emerging therapeutic opportunities, as well as the significant gaps that remain in this expanding field.