The selective expansion and growth advantage of malignant hematopoietic cells in CML may be related to their unresponsiveness to normal negative regulatory influences from the microenvironment. CML hematopoietic progenitors, in contrast to normal progenitors, demonstrate reduced beta1 integrin mediated adhesion to stroma and fibronectin. Since signaling through beta1 integrins inhibits normal hematopoietic progenitor proliferation, the continuous proliferation of CML progenitors adhering to stroma may be related to abnormal beta1 integrin mediated proliferation inhibition. We have demonstrated that interferon-alpha (IFN-alpha) treatment restores beta1 integrin mediated adhesion of CML progenitors to stroma and fibronectin, both directly as well as indirectly through enhanced stromal production of macrophage inflammatory protein-1alpha (MIP- 1alpha). We have further demonstrated that IFN-alpha also restores beta1 integrin mediated inhibition of CML progenitor proliferation. Our preliminary results suggest that abnormal beta1 integrin-mediated signaling in CML progenitors may be due to abnormalities in integrin- cytoskeleton interactions, and that IFN-alpha restores normal signaling through beta1 integrins in CML at least in part by restoring integrin-cytoskeletal interactions. We now propose studies directed towards understanding the mechanisms and significance of abnormal integrin function in CML, and its correction by IFN-alpha.
In Specific Aim l we will examine the molecular basis for the abnormal beta1 integrin dependent adhesion and signaling in CML hematopoietic progenitors and examine the mechanisms through which IFN-alpha corrects these defects. We hypothesize that the CML p210(BCR-ABL) tyrosine kinase induces perturbations in interactions between integrins, the cytoskeleton and associated signaling proteins which result in abnormal integrin function in CML, and that these abnormalities are reversed following IFN-alpha treatment.
In Specific Aim 2, we will examine the significance of restored beta1 integrin- mediated microenvironmental regulation of primitive and committed CML progenitor proliferation by IFN-alpha by examining the effects of IFN-alpha on the in vitro proliferation of primitive CML and normal hematopoietic progenitors and evaluating whether in vitro demonstration of restoration of normal beta1 integrin function in CML hematopoietic progenitors by IFN-alpha correlates with clinical hematological and/or cytogenetic responses to IFN-alpha therapy. These studies will enhance our understanding of CML pathogenesis, clarify mechanisms of action of IFN-alpha in CML and may lead to development of novel therapeutic strategies.
|Bhatia, R; Munthe, H A; Williams, A D et al. (2000) Chronic myelogenous leukemia primitive hematopoietic progenitors demonstrate increased sensitivity to growth factor-induced proliferation and maturation. Exp Hematol 28:1401-12|
|Bhatia, R; Munthe, H A; Verfaillie, C M (1999) Role of abnormal integrin-cytoskeletal interactions in impaired beta1 integrin function in chronic myelogenous leukemia hematopoietic progenitors. Exp Hematol 27:1384-96|
|Bhatia, R; Munthe, H A; Verfaillie, C M (1998) Tyrphostin AG957, a tyrosine kinase inhibitor with anti-BCR/ABL tyrosine kinase activity restores beta1 integrin-mediated adhesion and inhibitory signaling in chronic myelogenous leukemia hematopoietic progenitors. Leukemia 12:1708-17|
|Bhatia, R; Verfaillie, C M (1998) Inhibition of BCR-ABL expression with antisense oligodeoxynucleotides restores beta1 integrin-mediated adhesion and proliferation inhibition in chronic myelogenous leukemia hematopoietic progenitors. Blood 91:3414-22|