TREATMENT OF MARROW STROMA WITH INTERFERON-ALPHA RESTORES NORMAL BETA-1 INTEGRIN-DEPENDENT ADHESION OF CHRONIC MYELOGENOUS LEUKEMIA HEMATOPOIETIC PROGENITORS - ROLE OF MIP-1-ALPHA

The mechanisms by which interferon-alpha (IFN-alpha) restores normal hematopoiesis in chronic myelogenous leukemia (CML) are not well understood, We have recently demonstrated that IFN-alpha acts directly on CML hematopoietic progenitors to restore their adhesion to marrow stroma by modulating beta 1 integrin receptor function, In the present study we examined the effect of IFN-alpha treatment of marrow stroma on subsequent adhesion of CML progenitors, Stromal layers were preincubated with IFN-alpha (10,000 mu m/ml) for 48 h, Subsequent coincubation with CML progenitors for 2 h resulted in significantly increased adhesion of CML progenitors, We demonstrated that alpha 4 beta 1 and alpha 5 beta 1 integrin receptors were involved in the enhanced adhesion of CML progenitors, suggesting that IFN-alpha-treated stroma can upregulate CML integrin function, This effect is due, at least in part, to IFN-alpha-induced increased stromal production of the chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha), which upregulates beta 1 integrin-dependent adhesion of CML progenitors to stroma, Thus, IFN-alpha treatment of marrow stroma restores beta 1 integrin-dependent adhesion of CML progenitors, at least in part through induction of MIP-1 alpha production, These observations provide further insights into mechanisms by which IFN-alpha may restore normal hematopoiesis in CML.