Schematic describing the function of p27 in CML. (A) p27 distribution in CML cells. BCR-ABL1 degrades nuclear p27 in a kinase-dependent manner and promotes its cytoplasmic localization in a kinase-independent manner. (B) Complete loss of p27 (p27-null mutant). The absence of p27 promotes leukemogenesis, consistent with a net tumor-suppressive function of p27. (C) Nuclear stabilization of p27 (p27^T187A mutant). Stabilization of nuclear p27 as a result of the p27^T187A mutation only moderately attenuates leukemia because the oncogenic effect of cytoplasmic p27 persists. (D) Decreased p27 export to the cytoplasm (p27^S10A mutant). Reduced cytoplasmic p27 and increased nuclear p27 retention due to the p27^S10A mutation significantly reduces leukemogenesis of p27^S10A mice. (E) Functional cytoplasmic and nonfunctional nuclear p27 (p27^CK− mutant). The presence of functional cytoplasmic p27 and the complete absence of functional nuclear p27 in leukemic cells as a result of the p27^CK− mutation promote leukemogenesis. As we do not provide direct evidence for trafficking of nuclear p27 to the cytoplasm, a dashed line was used to suggest nuclear-cytoplasmic shuttling of p27.