15 research outputs found
The use of mouse models of normal and malignant hematopoiesis to design strategies for selective purging of primitive acute myeloid leukemia (AML) progenitors
The use of mouse models of normal and malignant hematopoiesis to design strategies for selective purging of primitive acute myeloid leukemia (AML) progenitors
A Diphtheria Toxin-Interleukin 3 Fusion Protein is Cytotoxic to Primitive Acute Myeloid Leukemia Progenitors but Spares Normal Progenitors.
The relative cytotoxicity of a diphtheria toxin (DT) human interleukin 3(IL3) fusion protein (DT388IL3) was tested against primitive normal (n = 3)and acute myeloid leukemia (AML) progenitors (n = 7). After 24-h culture with 50 ng/ml DT388IL3, the mean percentages of kill of AML colony-forming cells (CFCs), long-term culture-initiating cells (LTC-ICs), and suspension culture-ICs (SC-ICs) were 82% (range, 47–100), 56% (range, 28–91), and 74% (range, 43–87), respectively, with most surviving progenitors being cytogenetically normal. Engraftment of DT388IL-3-treated AML cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice followed for 16 weeks was eradicated for two of these samples. In contrast, with normal bone marrow, mean percentages of CFC kill of 49 and 64% were seen with 50 or 250 ng/ml DT388IL3, respectively, whereas no significant kills were observed in the LTC-IC and SC-IC assays. The NOD/SCID mouse repopulating cell (RC) frequency in normal BM cells was also not reduced by DT388IL3 treatment. In subsequent experiments, NOD/SCID mice that received AML blasts i.v. followed in 24 h by 0.045 μg/g DT388IL3 daily i.p. × 5 showed mean percentages of reduction in AML engraftment of 83% (range, 14–100) and 57% (range, 0–98) after 4 and 12 weeks, respectively (n = 6). No evidence of leukemia was detected with two of six AML samples 12 weeks after one 5-day course of DT388IL3. Repeating the DT388IL3 treatment every 4 weeks enhanced its effectiveness against two additional samples. Thus, DT388IL3 kills primitive leukemic progenitors from a proportion of AML patients but shows no significant toxicity against equivalent normal cells