Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines

Chronic myeloid leukemia (CML) is a malignant stem cell disease characteriz ed by an expansion of myeloid progenitor cells expressing the constitutivel y activated Bcr-Abl kinase, This oncogenic event causes a deregulation of a poptosis and cell cycle progression. Although the molecular mechanisms prot ecting from apoptosis in CML cells are well characterized, the cell cycle r egulatory event is poorly understood. An inhibitor of the cyclin-dependent kinases, p27, plays a central role in the regulation of growth factor depen dent proliferation of hematopoietic cells. Therefore, we have analyzed the influence of Bcr-Abl in the regulation of p27 expression in various hematop oietic cell systems, An active Bcr-Abl kinase causes down-regulation of p27 expression in murine Ba/F3 cells and human M07 cells, Bcr-Abl blocks up-re gulation of p27 after growth factor withdrawal and serum reduction. In addi tion, p27 induction by transforming growth factor-beta (TGF-beta) is comple tely blocked in Bcr-Abl positive M07/p210 cells. This deregulation is direc tly mediated by the activity of the Bcr-Abl kinase, A Bcr-Abl kinase inhibi tor completely abolishes p27 down-regulation by Bcr-Abl in both Ba/F3 cells transfected either with a constitutively active Bcr-Abl or with a temperat ure sensitive mutant. The down-regulation of p27 by Bcr-Abl depends on prot easomal degradation and can be blocked by lactacystin. Overexpression of wi ld-type p27 partially antagonizes Bcr-Abl-induced proliferation in Ba/F3 ce lls. We conclude that Bcr-Abl promotes cell cycle progression and activatio n of cyclin-dependent kinases by interfering with the regulation of the cel l cycle inhibitory protein p27, (C) 2000 by The American Society of Hematology.