STEM-CELL FACTOR ENHANCES THE ADHESION OF AML CELLS TO FIBRONECTIN AND AUGMENTS FIBRONECTIN-MEDIATED ANTI-APOPTOTIC AND PROLIFERATIVE SIGNALS

Acute myeloid leukaemia (AML) cells express the SCF receptor c-kit (CD 117) on their cell surface and demonstrate enhanced adhesion to fibron ectin (FN) following exposure to stem cell factor (SCF). Increased adh esion occurs within 5 min, is dose dependent, and persists beyond 2 h. Baseline and enhanced adhesion occur through the surface FN receptor very late antigen-5 (VLA-8, CD49e/CD29) which is expressed by AML cell s. Unstimulated AML cells exposed to FN undergo less apoptosis than co ntrols (inhibition 22.5 +/- 7.0%, P = 0.02, n = 8). Exposure to SCF al one without FN also inhibits AML cell apoptosis (by 19.0 +/- 7.7% comp ared to controls, P = 0.06, n = 8). Simultaneous exposure to SCF and F N increases the inhibition of AML cell apoptosis to 37.8 +/- 7.9% (P = 0.005 compared to control, P = 0.04 compared to FN alone, P = 0.06 co mpared to SCF alone) demonstrating that SCF not only enhances the prop ensity of AML cells to adhere to FN, but also results in an additive s urvival benefit following FN contact. Some but not all the reduction i n apoptosis is mediated through VLA-5. The combination of SCF and FN a lso affects proliferation, resulting in a synergistic enhancement of A ML cell proliferation in half the cases studied. When normal CD34(+) h uman haemopoietic progenitors were studied, FN had little effect on th eir apoptosis and failed to enhance the anti-apoptotic effect of SCF. It did, however, synergise with SCF in promoting CD34(+) cell prolifer ation. Exposure of AML cells to SCF and FN, both of which can be found in high concentration in the bone marrow stroma, inhibits apoptosis. Cytokines and extracellular matrix proteins augment each others' effec ts since SCF enhances adhesion to fibronectin, which in turn augments the survival signal delivered by the cytokine alone. Cytokine and adhe sion receptors can combine to affect cell characteristics including pr oliferation and survival.