1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Division of Hematology Oncology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
5. Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
6. Department of Biochemistry and Molecular Biology, University of Louisville, Kentucky 40292, USA
7. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

Correspondence to: Todd R. Golub^1,2,7 Correspondence and requests for materials should be addressed to T.R.G. (Email: golub@broad.mit.edu).

Somatic chromosomal deletions in cancer are thought to indicate the location of tumour suppressor genes, by which a complete loss of gene function occurs through biallelic deletion, point mutation or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis¹. In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q^- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation². Here we describe an RNA-mediated interference (RNAi)-based approach to discovery of the 5q^- disease gene. We found that partial loss of function of the ribosomal subunit protein RPS14 phenocopies the disease in normal haematopoietic progenitor cells, and also that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond–Blackfan anaemia, linking the molecular pathophysiology of the 5q^- syndrome to a congenital syndrome causing bone marrow failure. These results indicate that the 5q^- syndrome is caused by a defect in ribosomal protein function and suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.

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