Therapeutic progress in aggressive myeloid malignancies such as acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and advanced myeloproliferative neoplasm (MPNs) has been slow. This is partially due to the heterogeneity of the diseases and the lack of molecular understanding, which delays effective drug development. There will be potentially three rather effective avenues to arrive at novel molecular vulnerabilities that can be therapeutically exploited. First, is identifying disease-specific mutations or other genomic aberrations (i.e. translocations, aberrant methylation) that will result in targeting affected and closely associated genes. Second, is tracing disease evolution over time, clonal evolution by various approaches, many of which will include current genomic tools and assays. Third, a more unbiased, broad discovery approach either with small molecule screens or, in our opinion, by identification of specific molecular vulnerabilities by RNA interference (RNAi). RNAi is a mechanistically rather agnostic high-throughput approach to find essential targets, alone or in combination with commonly used anti-cancer agents. In this paper we will briefly summarise some ideas and early results of RNAi screens, with a focus on hypomethylating agents and how RNAi can identify rational combination therapies with 5-azacytidine that can be rapidly translated into the clinical setting.
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