Human leukemia is distinguished by a relatively low rate of p53 mutation, possibly enabling pharmacological activation of WT p53 for therapy. CKI ablation offers robust means of p53 activation, which has successfully been tested in leukemia cells in vitro and underlies the therapeutic effect of lenalidomide in human MDS pre-leukemia syndrome. However, with no selective CKI inhibitors available for in vivo use, the therapeutic value of CKI inhibition in hematological malignancies cannot be validated. I will describe the development of such inhibitors and show that they are highly efficient in controlling leukemia in mouse models, while sparing normal hematopoiesis.
