Semin Hematol. 2026 Sep 16. pii: S0037-1963(26)00087-9. [Epub ahead of print]
Translational control has emerged as a critical layer of gene expression reprogramming in cancer, with the ribosome functioning as a central regulatory node rather than a passive protein synthesis machinery. This review provides an integrated overview of how defects in ribosomes and translational regulation contribute to the pathogenesis of lymphoid leukemias and lymphomas. We focus on 3 major axes: mutations in ribosomal proteins, alterations in ribosomal RNA, and dysregulation of translation initiation mediated by the eukaryotic initiation factor 4F complex. Recurrent mutations in ribosomal proteins, such as RPL10 in T-cell acute lymphoblastic leukemia and RPS15 in chronic lymphocytic leukemia, alter ribosome function, leading to selective changes in mRNA translation, impaired translational fidelity, and increased oxidative stress that promotes genomic instability. In parallel, emerging evidence indicates that alterations in ribosomal RNA, including changes in ribosomal DNA copy number, biogenesis, and epigenetic modifications, contribute to ribosome heterogeneity and oncogenic transformation, although their precise roles in hematologic malignancies remain incompletely understood. Furthermore, aberrant activation of translation initiation pathways-often driven by the AKT/mTOR/MYC signaling axis-enhances both global protein synthesis and selective translation of oncogenic transcripts, reinforcing malignant phenotypes. Together, these ribosome-intrinsic and -extrinsic defects converge to reprogram the translatome, promote tumor progression, and create therapeutic vulnerabilities. Targeting translational control mechanisms therefore represents a promising strategy for the treatment of lymphoid malignancies.
Keywords: Chronic lymphocytic leukemia; Ribosomal protein mutations; Ribosome biogenesis; T-cell acute lymphoblastic leukemia; eIF4F; rRNA