CML is caused by the BCR/ABL gene rearrangement. The oncogene gives rise to a 210 kD fusion protein [p210BCR'BL] which, compared with the p!45ABL protein, is located exclusively in the cell cytoplasm, binds significantly better to the actin cytoskeleton and has increased tyrosine kinase activity leading to the activation of the Ras/MapK/JunK pathway and phosphorilation of a number of cytoplasmic molecules, including paxillin, tensin, Fak, CrkL, Stat-5. Although the molecular consequences of BCR/ABL are well understood, it is unclear how these molecular alterations lead to the clinical syndrome of CML. CML is characterized by an abnormal expansion and premature circulation in the blood of mainly granulocytic progenitors and precursors. This is due in part to decreased βl- integrin mediated interactions of Ph progenitors with the BM microenvironment. Although (x4βl and a5βl integrins are expressed on CML progenitors, they fail to adhere to BM stroma and the ECM component, fibronectin. In NL hematopoiesis adhesion through βI-integrins is not only responsible for localization of progenitors in the microenvironment, bui we have shown that they also transfer signals that inhibit progenitor proliferation. In CML, in contrast, engagement of integrins does not affect progenitor proliferation. Thus, defects in integrin dependent adhesion may not only explain the abnormal trafficking of Ph+ progenitors in the blood but also at least in part the uncontrolled expansion of the Ph clone. Since treatment of Ph progenitors with IFNa or an βl-integrin-activating antibody restores integrin dependent adhesion and growth inhibitory signaling, integrins in CML seem to be functionally rather than structurally defective. We have evidence that the defective function of βl-integrins is due to the presence of p210BCRMBL tyrosine kinase: elimination of p210BCR/ABL by antisense oligo nucleotides or inhibition of the p210 kinase function by tyrphostins restores integrin dependent adhesion and proliferation inhibition. As βl integrins fail to laterally associate on CML progenitors, integrin-cytoskeletal interactions seem to be defective either as a result of binding between p210BCEMBL and F-actin or of the chronic phosphorilation of cytoskeletal associated signal molecules such as paxillin, tensin or Fak. Studies will be presented that characterize these functional abnormalities of integrins in CML.