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 the marrow microenvironment. Normal progenitors adhere through a variety of receptors to stroma and extracellular matrix components, including fibronectin. Adhesion through beta1-integrin receptors to fibronectin not only anchor progenitors to the stroma but also result in direct adhesion-mediated signaling that inhibits progenitor proliferation. In contrast to normal hematopoiesis, chronic myelogenous leukemia (CML) is characterized not only by abnormal, premature circulation of primitive progenitors in the blood but 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 of 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 interferon-alpha or an activating anti-beta1-integrin antibody suggests a functional rather than structural defect that may be related to 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 lead to novel therapeutic approaches.
Verfaillie
C M
CM
Department of Medicine, University of Minnesota, Minneapolis 55455, USA.
Hurley
R
R
Zhao
R C
RC
Prosper
F
F
Delforge
M
M
Bhatia
R
R
D000818:Animals; D002448:Cell Adhesion; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000503:physiopathology*; D008954:Models, Biological
D016023:Integrins; D016044:Fusion Proteins, bcr-abl