From ribosomopathies to therapeutic targets: ribosomal alterations in pediatric leukemogenesis and tumorigenesis

Ribosomes are central to cellular growth and proteome maintenance, and cancer cells frequently depend on increased ribosome biogenesis and altered translation to sustain proliferation, stress tolerance, and metabolic rewiring. Paradoxically, inherited "ribosomopathies" caused by germline defects in ribosomal proteins or ribosome biogenesis factors present with tissue hypoplasia and bone marrow failure early in life, yet confer substantially increased lifetime risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. In parallel, somatic alterations affecting ribosomal proteins and ribosome regulatory pathways recur across malignancies, including hematologic cancers such as T-cell acute lymphoblastic leukemia (T-ALL), and in pediatric solid tumors. Mechanistically, oncogenic ribosome disturbances can reprogram translation toward specific mRNA subsets, alter translational fidelity, trigger nucleolar/ribosomal stress signaling via the 5S ribonucleoprotein (5S RNP)-MDM2-p53 axis, and enable selection for compensatory or cooperating lesions (notably TP53 pathway alterations). Clinically, these insights support diagnostics and surveillance of inherited ribosome-related cancer predisposition syndromes, therapeutic targeting of ribosome biogenesis and translational control, including RNA polymerase I inhibition, and the eIF4 translation-initiation machinery. Here, we present current evidence linking constitutional and acquired ribosomal dysfunction to leukemogenesis and tumorigenesis, highlight disease- and context-specific mechanisms, and outline priorities for translational research and precision therapy.