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अमूर्त

Impaired Ribosome Biogenesis and P53 Activation in Haematological Disease: Novel Therapeutic Strategies

Calum Leitch, Vibeke Andresen and Bjørn Tore Gjertsen

Hereditary forms of bone marrow failure and aplastic anaemia (AA) manifest in rare blood syndromes (Dyskeratosis Congenita, Diamond-Blackfan Anaemia and Shwachman-Diamond Syndrome) in which genetic abnormalities directly impair ribosome biogenesis. These conditions are all associated with varying degrees of predisposition to haematological malignancy. Various studies of ribosome proteins have revealed an intimate relationship between ribosome biogenesis and p53 that governs cell fate in human haematopoietic disease. Over 70 years ago, recognition of the bone marrow suppressive properties of nitrogen mustards led to the development of early chemotherapeutics. Since, a multitude of seemingly unrelated drugs have emerged that also provoke AA as an idiosyncratic side effect. Here we hypothesize that at least some of these bone marrow suppressive drugs target ribosome biogenesis thereby mimicking congenital forms of bone marrow failure and inducing AA. If so, these bone marrow suppressive drugs may also share the anti-cancer potential of mustard gas through targeting abnormal ribosome biogenesis in malignant haematopoietic stem cells. Targeted drug development is an arduous and time-consuming process, however, repurposing of bone marrow suppressive drugs could provide a novel, clinically applicable therapeutic strategy in haematological malignancies.