INTEGRIN-MEDIATED REGULATION OF HEMATOPOIESIS - DO BCR ABL-INDUCED DEFECTS IN INTEGRIN FUNCTION UNDERLIE THE ABNORMAL CIRCULATION AND PROLIFERATION OF CML PROGENITORS/

Hematopoiesis takes place in close contact with the marrow microenviro nment, Normal progenitors adhere through a variety of receptors to str oma and extracellular matrix components, including fibronectin. Adhesi on through integrins to fibronectin may not only serve to anchor proge nitors to the microenvironment but also to directly alter the prolifer ative behavior of normal hematopoietic progenitors, Chronic myelogenou s leukemia (CML) is a malignant disease of the hematopoietic stem cell . At the molecular level, CML is characterized by the BCR/ABL gene rea rrangement which encodes for the oncoprotein, p210(bcr-abl), Presence of the p210(bcr-abl) tyrosine kinase is necessary and sufficient for t he malignant transformation of hematopoietic cells, Clinically, CML is characterized by an abnormal, premature release of primitive progenit ors and precursors in the blood and by the continuous proliferation. o f the malignant progenitor population, In vitro, CML progenitors fail to adhere to or be regulated by marrow stroma, Since CML progenitors e xpress similar numbers of integrin adhesion receptors as normal progen itors, functional rather than quantitative differences of these recept ors on CML progenitors may be responsible for the abnormal circulation and proliferation of the malignant clone, In this manuscript we will review the role of integrin adhesion receptors present on normal hemat opoietic progenitors in the regulation of their proliferation and disc uss signal transduction mechanisms that may be responsible for these e ffects, We will also discuss the integrin defect in CML which may be c aused by the presence of the oncoprotein, P210(bcr-abl), and may expla in the abnormal trafficking and proliferation observed in CML.