THE BCR-ABL TYROSINE KINASE ACTIVATES MITOGENIC SIGNALING PATHWAYS AND STIMULATES G1-TO-S PHASE-TRANSITION IN HEMATOPOIETIC-CELLS

Bcr-Abl is a constitutively active tyrosine kinase that is expressed i n Philadelphia chromosome (Ph-1)-positive human leukemias. Bcr-Abl has been shown to inhibit apoptosis and cause anchorage independent growt h. However, its ability to activate mitogenic signaling pathways is co ntroversial. Here we show that Bcr-Abl signaling prevents down-regulat ion of cyclin-dependent kinase activity and cell cycle arrest after gr owth factor deprivation of hematopoietic progenitor cells, Using an in ducible system to regulate Bcr-Abl expression, we also demonstrate tha t Bcr-Abl expression is sufficient to induce G1-to-S phase transition, DNA synthesis, and activation of cyclin-dependent kinases in cells th at were arrested in G(0) by growth factor deprivation, Furthermore, Bc r-Abl activates Pas, Erk, and Jnk pathways as a primary consequence of expression. These data show that Bcr-Abl is one of a select group of oncogenes that is capable of both inhibiting apoptosis and deregulatin g cell proliferation. The combination of these activities is likely to be important for the progression of CML.