Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML.

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Taken together, the data reported by Cazzaniga et al. and our results consistently show that in pediatric patients, NPM1 mutations are less common than in adults and tend to affect older patients. Preliminary data also indicate that NPM1 mutations might be associated with favorable outcome, which warrants further studies to address this question. In addition, our results point to an effect of age on the prevalence of different NPM1-mutations, with non-typical (i.e. non-type A) mutations being most prevalent in children and younger adults. The reason for this association is unknown, but might refer to different molecular mechanisms involved in the development of this abnormality, a process which is currently largely unclear. This finding has also important implications for the MRD analysis and molecular follow-up of pediatric cases with NPM1 þ AML. Whereas in adults, type A mutations predominate and assays focusing on this type will be suitable in most cases, in pediatric patients mutations should always be analyzed by sequencing. In these cases, a recently reported LNA-based procedure might be advantageous for follow-up of residual disease after treatment.