Truncating mutations of PPM1D found in myeloid malignancies lead to loss of the C-terminal degradation domain, resulting in increased levels of PPM1D. Increased PPM1D activity results in inhibition of TP53 that enhances the fitness of both normal and malignant HSCs. Leukemia HSCs that have high PPM1D activity are resistant to chemotherapy. Although PPM1D inhibition alone does not have significant activity against leukemia cells, it is synergistic with chemotherapy. Professional illustration by Patrick Lane, ScEYEnce Studios.