Polycomb segment myeloid malignancies to the tyrosine kinase inhibitors that have changed the paradigm of CML treatment, was within reach. Six years later, the first JAK2 inhibitor, Ruxolitinib, has gained FDA approval but, while very effective at ameliorating disease symptoms, it does not appear to alter the natural history of these diseases. In particular, its effect on JAK2V617F allele burden, widely assumed to reflect the size of the neoplastic clone, is limited. 7 Therefore, novel strategies, most likely involving novel targets, are required to foster the development of innovative therapies for MPN patients. Because, as demonstrated by the use of a pan-CDC25 inhibitor in this study, the phosphatase CDC25A is amenable to pharmacologic inhibition, and healthy hematopoiesis appears largely unaffected by this intervention, the paper by Gautier et al provides a promising lead toward the exploration of alternative targets for rational drug design in MPN treatment.