PI3-Kinase may be involved in cml progenitor cell responses to interferon alfa and STI571

We investigated whether PI-3 kinase is involved in responses of CML progenitor cells to interferon(IFN)-α and STI571 and/or biological abnormalities in CML. We used a colony (CFU-GM) replating assay, to measure the self-renewal capacity of CFU-GM, expressed as the area-under-the-curve (AUC) of the distribution of secondary CFU-GM numbers. The AUC is greater for CML than for normal CFU-GM (p=0.029). Using an aggregation assay, we found that the aggregation index (AI) of CD34+ cells in the presence of QBEND10 antibody is subnormal in CML IFN-α and STI571 reduce the AUC of CML CFU-GM and increase the AI of CD34+ CML cells. This agrees with our finding that AUC and AI are inversely related. We evaluated the role of PI3-kinase by performing experiments in the presence of 1.0 μM, wortmannin (WM), a PI3-kinase inhibitor. WM reduced the AUC to 77–8% (mean–sem; n=13) of control levels. This result was not significantly different from the effects of IFN-α or STI571 (p=0.87 and 0.38). However, the individual responses to WM correlated better with response to STI571 (r=0.68) than with response to IFN-α (r=0.48). WM increased the AI of CML CD34+ cells 2.5–0.35-fold (n=8). This was not significantly different from the effects of IFN-α or STI571 (p=0.63 and 0.14). The responses to WM and IFN-α in the aggregation assay did not correlate (r=0.0) whilst those to WM and STI571 did (r=0.95). We conclude that (1) IFN-α and STI571 influence the same biological functions in CML but may operate through different biochemical pathways; (2) the PI-3 kinase pathway is more important for responses to STI571 than for responses to IFN-α and (3) the PI-3 kinase pathway can modulate progenitor proliferation and aggregation in CML.