Identification of new candidate drugs in myelodysplastic syndromes with splicing factor mutations by transcriptional profiling and connectivity map analysis.

We sought to identify new candidate drugs for repurposing to myelodysplastic syndromes (MDS). Connectivity map analysis was performed on gene expression signatures generated from bone marrow CD34⁺ cells of splicing factor mutant MDS patients. Celastrol and Withaferin A (WA), two top-ranking compounds identified, markedly inhibited proliferation, arrested the cell cycle and induced apoptosis in leukaemia cells. These compounds also inhibited the viability of primary bone marrow MDS cells. We showed that Celastrol and WA inhibit interleukin-1 receptor-associated kinase 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signalling activation in splicing factor mutant MDS and leukaemia cells. Celastrol and WA may represent novel candidate drugs for the treatment of MDS.