Interferon-α restores normal β1 integrin-mediated inhibition of hematopoietic progenitor proliferation by the marrow microenvironment in chronic myelogenous leukemia

Academic Article

Abstract

  • Chronic myelogenous leukemia (CML) progenitors show decreased adhesion to stroma and fibronectin (FN) through β1 integrin receptors. We have previously shown that interferon-α (IFN-α) restores β1 integrin-mediated adhesion of CML progenitors to stroma. Because β1 integrins transmit proliferation inhibitory signals from the microenvironment to normal hematopoietic progenitors, we hypothesized that decreased integrin-mediated adhesion of CML progenitors contributes to their continuous proliferation when in contact with stroma and that IFN-α treatment, by restoring integrin- mediated adhesion, also restores integrin-mediated microenvironmental inhibition of CML progenitor proliferation. We show here that, in contrast to normal colony-forming cells (CFC), the percentage of malignant CML CFC in S- phase was not significantly reduced following coculture with stromal layers. However, IFN-α treatment resulted in a significant reduction in the proliferation of CML CFC on coculture with stroma. This effect was not because of a direct antiproliferative effect of IFN-α on CML CFC because the proliferation of IFN-α-treated CML CFC kept in suspension culture was not reduced. We examined the role of restored signaling through β1 integrin receptors in IFN-α induced inhibition of CML progenitors in two sets of experiment. In the first set of experiments, we demonstrated that proliferation of IFN-α-treated CML CFC, but not untreated CML CFC, was significantly reduced following coculture with 33/66-kD and 75-kD FN fragments, recognized by β4β1 and α5β1 integrins respectively. In a second set of experiments, we demonstrate that direct stimulation of integrin receptors by crosslinking with blocking antibodies to α4, α5, and β1 integrins and secondary goat antimouse antibodies resulted in significant reduction in proliferation of normal and IFN-α treated CML progenitors but not untreated CML CFC. These studies indicate that CML hematopoietic progenitors are unresponsive to β1-integrin mediated proliferation inhibition and that IFN-α not only restores β1 integrin-mediated adhesion but also β1-integrin-mediated microenvironmental inhibition of CML progenitor proliferation. These observations may explain, at least in part, the therapeutic efficacy of IFN-α in CML
  • Author List

  • Bhatia R; McCarthy JB; Verfaillie CM
  • Start Page

  • 3883
  • End Page

  • 3891
  • Volume

  • 87
  • Issue

  • 9