Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34 ⁺ cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27 Kip , which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity

β 1 -integrin engagement on normal (NL) CD34 + cells increases levels of the cyclin-dependent kinase inhibitor (cdki), p27 Kip , decreases cdk2 activity, and inhibits G 1 /S-phase progression. In contrast, β 1 -integrin engagement on chronic myelogenous leukemia (CML) CD34 + cells does not inhibit G 1 /S progression. We now show that, in CML, baseline p27 Kip levels are significantly higher than in NL CD34 + cells, but adhesion to fibronectin (FN) does not increase p27 Kip levels. p27 Kip mRNA levels are similar in CML and NL CD34 + cells and remain unchanged after adhesion, suggesting posttranscriptional regulation. Despite the elevated p27 Kip levels, cdk2 kinase activity is similar in CML and NL CD34 + cells. In NL CD34 + cells, >90% of p27 Kip is located in the nucleus, where it binds to cdk2 after integrin engagement. In CML CD34 + cells, however, >80% of p27 Kip is located in the cytoplasm even in FN-adherent cells, and significantly less p27 Kip is bound to cdk2. Thus, presence of BCR/ABL induces elevated levels of p27 Kip and relocation of p27 Kip to the cytoplasm, which contributes to the loss of integrin-mediated proliferation inhibition, characteristic of CML.