Stem cell factor and chronic myeloid leukemia CD34+cells

Normal hematopoiesis is a tightly regulated process involving a balance bet ween signals that stimulate and those that inhibit the proliferation and di fferentiation of hematopoietic progenitors. In chronic myeloid leukemia (CM L) there is a perturbation of these controlling elements, resulting in over growth of leukemic cells in the bone marrow and spleen. In part, the prolif eration of CML CD34+ cells may result from an abnormal response to the cyto kine Stem Cell Factor (SCF). SCF induced proliferation and adhesion to the extracellular matrix via fibronectin are not coupled in CML as they are in normal cells and this may contribute to the accumulation of leukemic progen itors. We have previously shown that CD34+ CML cells and the more primitive CD34+CD38- CML cells do not require the addition of synergistic cytokines to cultures, but are capable of proliferation in SCF alone, and that leukem ic CFU-GM are selectively supported in these cultures. In the presence of o ther cytokines the response of CML cells to SCF is no greater than that of cells from normal donors, suggesting that the leukemic cells are not more s ensitive to SCE but that accessory pathways are already activated in these cells. Cells from patients with myeloproliferative disorders show variable proliferative response to SCF as the sole mitogenic stimulus, suggesting th at expression of bcr-abl is essential for proliferation in this cytokine. F urther studies to identify the key determinants of the abnormal response to SCF in CML may lead to a better understanding of the proliferative abnorma lity that underlies CML.