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

beta(1)-integrin engagement on normal (NL) CD34(+) cells increases levels o f the cyclin-dependent kinase inhibitor (cdki), p27(Kip), decreases cdk2 ac tivity, and inhibits G(1)/S-phase progression. In contrast, beta(1)-integri n engagement on chronic myelogenous leukemia (CML) CD34(+) cells does not i nhibit G(1)/S progression. We now show that, in CML, baseline p27(Kip) leve ls are significantly higher than in NL CD34(+) cells. but adhesion to fibro nectin (FN) does not increase p27(Kip) levels. p27(Kip) mRNA levels are sim ilar in CML and NL CD34(+) cells and remain unchanged after adhesion, sugge sting 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 le ss p27(Kip) is bound to cdk2. Thus, presence of BCR/ABL induces elevated le vels of p27(Kip) and relocation of p27(Kip) to the cytoplasm, which contrib utes to the loss of integrin-mediated proliferation inhibition, characteris tic of CML.