Vitamin K-2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation

We have previously reported that vitamin K-2 (VK2) has a potent apoptosis i nducing activity toward various types of primary cultured leukemia cells in cluding acute myelogenous leukemia arising from myelodysplastic syndromes ( MDS). We established a novel cell line, designated MDS-KZ, from a patient w ith MDS in blastic transformation, and further investigated the effects of VK2 using this novel cell line. MDS-KZ shows complex chromosomal anomaly in cluding -4, 5q-, -7, 13q+, 20q-, consistent with that seen in the original patient. Culture of MDS-KZ cells in RPMI1640 medium containing 10% FBS lead to steady but very slow proliferation with a doubling time of 14 days. How ever, the cellular growth rate was significantly accelerated in the presenc e of various growth factors such as granulocyte colony-stimulating factor, stem cell factor, granulocyte-macrophage colony-stimulating factor, interle ukin-l, and thrombopoietin. Most of the cultured cells show the morphologic al features of myeloblasts. They are positive for CD7, CD33, CD34, CD45, CD 117, and HLA-DR. However, about 10% of the cells are more mature metamyeloc ytes and neutrophils with various dysplastic characteristics such as pseudo -Pelger nuclear anomaly and hypersegmentation, suggesting a potential for d ifferentiation in this cell line. As previously reported for cultured prima ry leukemia cells, exposure to VK2, but not to VK1, resulted in induction o f apoptosis of MDS-KZ cells in a dose-dependent manner (IC50: 5 mu M). In a ddition, VK2 treatment induced down-regulation of BCL-2 and up-regulation o f BAX protein expression with concomitant activation of caspase-3 (CPP32). A tetrapeptide functioning as antagonist of caspase-3, Ac-DEVD-H, suppresse d the VK2-induced inhibition of cell growth, suggesting that caspase-3 is, at least in part, involved in VK2-induced apoptosis. These observations sug gest that the MDS-KZ cell line can serve as a model for the study of the mo lecular mechanisms of VK2-induced apoptosis.