Ribosomopathies and the paradox of cellular hypo- to hyperproliferation

Abstract

Ribosomopathies are largely congenital diseases linked to defects in ribosomal proteins or biogenesis factors. Some of these disorders are characterized by hypoproliferative phenotypes such as bone marrow failure and anemia early in life, followed by elevated cancer risks later in life. This transition from hypo- to hyperproliferation presents an intriguing paradox in the field of hematology known as "Dameshek's riddle." Recent cancer sequencing studies also revealed somatically acquired mutations and deletions in ribosomal proteins in T-cell acute lymphoblastic leukemia and solid tumors, further extending the list of ribosomopathies and strengthening the association between ribosomal defects and oncogenesis. In this perspective, we summarize and comment on recent findings in the field of ribosomopathies. We explain how ribosomopathies may provide clues to help explain Dameshek's paradox and highlight some of the open questions and challenges in the field.

Figure 1

Model explaining transition from hypo- to hyperproliferation phenotypes in ribosomopathies. (A) In the initial phase of the disease, a mutation in a ribosomal protein or ribosome biogenesis factor (symbolized by the red star on the 60S subunit) impairs proper ribosome biogenesis, resulting in lower concentrations of assembled ribosomes. This ribosome biogenesis defect impairs proper proliferation of the cells by activating the TP53 pathway and/or by TP53 independent mechanisms. At this stage, functional ribosomes are still assembled to a certain extent. These ribosomes are however intrinsically defective, and may induce translational changes/shifts in the cells. (B-C) The impaired proliferation imposes strong pressure on cell populations, selecting for cells that acquire a compensatory mutation rescuing the impaired proliferation. The nature of this compensatory mutation is currently unclear. Cells may acquire a mutation in a biogenesis factor rescuing the biogenesis defect (B). Alternatively, the signaling pathways inducing the proliferation impairment upon a biogenesis defect (TP53 or other) may be crippled by a compensatory mutation (C). In both scenarios, after acquiring the compensatory mutation, defective ribosomes would still be formed that alter the translational capacity/fidelity leading to the cell obtaining a clonal advantage over other cells. However, these ribosomes are intrinsically defective, leading to altered gene expression programs. Dashed arrows indicate the more speculative parts.