The effect of interferon-alpha on beta-1 integrin mediated adhesion and growth regulation in chronic myelogenous...

There is considerable interest in understanding the mechanisms by which interferon-alpha can induce hematological and cytogenetic remissions and prolong survival in patients with chronic myelogenous leukemia (CML). There is evidence that the selective expansion and growth advantage of malignant hematopoietic progenitors in CML may be related, at least in part, to their deficient responsiveness to normal negative regulation by the marrow stromal microenvironment and that interferon-alpha may restore normal hematopoiesis in CML by restoring normal microenvironmental regulation of malignant CML progenitor proliferation. In normal hematopoiesis, beta1 integrin receptors mediate progenitor adhesion to stroma. Stimulation of beta1 integrin receptors on normal progenitors results in transmission of proliferation inhibitory signals. CML progenitors demonstrate defective beta1 integrin receptor-mediated adhesion and regulation of proliferation. We have shown that interferon-alpha can restore both beta1 integrin mediated adhesion as well as integrin-mediated proliferation inhibition of CML progenitors. Interferon-alpha enhances CML integrin function through direct effects on CML progenitors as well as indirect effects on stroma. Restored beta1 integrin-mediated regulation of malignant CML progenitor proliferation may result in restoration of normal hematopoiesis in CML patients treated with interferon-alpha. There is evidence that abnormal integrin mediated signaling in CML progenitors may result from abnormalities in integrin-cytoskeletal interactions induced by the p210BCR/ABL tyrosine kinase. Although the exact mechanisms by which interferon-alpha restores normal integrin signaling in CML are not known, preliminary studies indicate that this may at least partly be related to the restoration of normal integrin-cytoskeletal interactions. The above studies offer some insights into the mechanisms of abnormal hematopoietic regulation in CML and the mechanisms by which interferon-alpha may restore normal hematopoiesis, in this disease.