It has long been known that cancer cells display enlarged nucleoli and elevated rates of ribosomal gene (rDNA) transcription and protein
synthesis. However whether ribosomal gene transcription is required for
the malignant phenotype is unclear. Using genetic approaches and the the small molecule CX-5461 we demonstrate that EµMYC lymphoma cells are exquisitely sensitive to inhibition of rDNA transcription. In contrast wild type B-cells remain viable following inhibition of rDNA transcription. The therapeutic benefit to CX-5461 is consequence of rapid nucleolar disruption and activation of p53 signalling. Malignant human haematological cell lines also show similar sensitivity to CX-5461. To evaluate the potential of this approach for the treatment of human cancer we have designed a phase I trial to evaluate the safety, efficacy, target inhibition and selectivity for malignant over non-malignant cells of CX-5461 in patients with haematological malignancies. We propose that selective inhibition of rDNA transcription is a therapeutic strategy that may allow cancer specific activation of p53.