[A preliminary study on mechanisms for resistance of CML patient BM-derived bcr/abl+ and Flk1+CD31-CD34- stem cells to STI571 in vitro]

Abstract

To evaluate the effect of imatinib mesylate (STI571) on primitive/committed malignant progenitor cells in chronic myelogenous leukemia (CML) and to further elucidate the mechanisms involved in CML relapse and in some CML cells resistant to STI571, bone marrow-derived malignant bcr/abl-positive, Flk1(+)CD31CD34(-) cells with hemangioblastic characteristics from CML patients were grown in Methocult GF+ media with or without STI571, and inhibitory effect of STI571 on proliferation of differentiated and differentiating, bcr/abl(+), Flk1(+)CD31CD34(-) cells with hemangioblastic characteristics was investigated in vitro. The results showed that in vitro exposure to 5 micromol/L STI571 (the concentration of STI571 usually achieved in patients is 1-2 micromol/L) for 96 hours inhibited bcr/abl(+) committed progenitors (colony-forming cells, CFCs). No evident suppression of normal primitive, bcr/abl(+), and Flk1(+)CD31(-)CD34(-) cells were observed. It is concluded that CML primitive stem cells remain viable in the presence of STI571 and that inhibition of bcr/abl tyrosine kinase by STI571 restores normal hematopoiesis by removing the proliferative advantage of CML committed progenitors but that elimination of all CML progenitors may not occur. So despite dramatic short-term responses in vivo, such in vitro resistance to STI571, may translate into disease relapse after prolonged therapy.