Pathophysiology of CML: Do defects in integrin function contribute to the premature circulation and massive expansion of the BCR/ABL positive clone?

Hematopoiesis takes place in close contact with She marrow microenvironment. Normal progenitors adhere through a variety of receptors 50 stroma and extracellular matrix components, including fibronectin. Adhesion through beta 1-integrin receptors to fibronectin not only anchor progenitors So the stroma but also result in direct adhesion-mediated signaling that inhibits progenitor proliferation. In contrast to normal hematopoiesis, chronic myelogenous leukemia (CMI) is characterized not only by abnormal, premature circulation of primitive progenitors in the blood bat also by continuous progenitor proliferation. although CML progenitors express the same integrin receptors as normal progenitors, they fail to adhere to stroma and fibronectin, suggesting structural or functional abnormalities sf these receptors. Furthermore, CML cells present in contact with stroma or fibronectin continue to proliferate, suggesting that failure to adhere through integrin receptors may also underlie the abnormal proliferation of CML progenitors, The observation that integrin-mediated adhesion and proliferation-inhibitory signaling can be restored through treatment with inferferon-alpha or an activating anti-beta 1-integrin antibody suggests a functional rather than structural defect that may be related Is the presence of the BCR/ABL gene rearrangement in these cells, insights into the role of integrins as adhesion molecules but also receptors that instruct hematopoietic progenitors to survive, proliferate, and possibly differentiate will not only further our understanding of the normal hematopoietic process but also provide insights into diseases characterized by deranged adhesion and proliferation that may Bead to novel therapeutic approaches.