Chronic myelogenous leukemia primitive hematopoietic progenitors demonstrate increased sensitivity to growth factor-induced proliferation and maturation

Objective. We investigated whether primary chronic myelogenous leukemia (CM L) hematopoietic progenitors demonstrated altered proliferation and maturat ion in response to growth factor (GF) stimulation. Methods. The effect of GF stimulation on proliferation and expansion of com mitted and primitive progenitors (colony forming cells [CFC]) was evaluated . Results. Culture of CML and normal CD34(+) cells with different GF for 7 da ys resulted in similar expansion of committed progenitors (CFC). In contras t, GF culture conditions that expanded normal primitive progenitors (week-6 long-term culture-initiating cells (LTC-IC)] led to depletion of CML LTC-I C numbers. GF culture also resulted in increased depletion of week-10 exten ded LTC-IC, which represent an even more primitive progenitor population, f rom CML compared with normal CD34(+) cells. CR IL CD34(+) cells enter into cycle more quickly than normal CD34(+) cells and CML CFC expansion was acce lerated compared to normal CFC, Evaluation of primitive progenitor prolifer ation using PKH-26 and single-cell LTC-IC analysis demonstrated that the ma jority of CML LTC-IC remaining after GF culture originated from divided CD3 4(+) cells, whereas GF-cultured normal LTC-IC were derived mainly from undi vided cells. Depletion of CML primitive progenitor numbers in association w ith increased proliferation suggests increased sensitivity to GF-induced ma turation. Conclusions. These studies indicate that CML primitive progenitors have enh anced sensitivity to GF-induced cell division and maturation. Altered GF re sponsiveness may contribute to abnormal expansion of malignant myeloid cell s in CML. These findings may also be applied toward the development of nove l approaches to select benign stem cells in CML. (C) 2000 International Soc iety for Experimental Hematology. Published by Elsevier Science Inc.