MALIGNANT PROGENITORS FROM PATIENTS WITH ACUTE MYELOGENOUS LEUKEMIA ARE SENSITIVE TO A DIPHTHERIA TOXIN-GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR FUSION PROTEIN

We have previously demonstrated that human granulocyte-macrophage colo ny-stimulating factor (GM-CSF) fused to a truncated diphtheria toxin ( DT388-GMCSF) kills acute myelogenous leukemia (AML) cell lines bearing the GM-CSF receptor. We now report that exposure of malignant cells f rom 50 different patients with AML for 48 hours in culture to DT388-GM CSF reduces by a median of 1.6 logs (range, 0 to 3.7 logs) the number of leukemic cells capable of forming colonies in semisolid media (leuk emic colony-forming cells [CFU-L]) with a median IC50 of 3 x 10(-12) m ol/L (range, 5 to > 4,000 x 10(-12) mol/L), Furthermore, the cell kill is dependent on the presence of high-affinity GM-CSF receptors on leu kemic blasts, because CFU-L from 27 of 28 AML samples expressing great er than or equal to 35 GM-CSF receptors per cell were inhibited by the toxin, whereas the colony growth from all 4 leukemic samples (2 AML, 1 acute lymphoblastic leukemia [ALL], and 1 prolymphocytic leukemia [P LL]) that had less than 35 receptors per cell was unaffected by the dr ug. Sensitivity of CFU-L to DT388-GMCSF was seen regardless of the cli nical responsiveness of the patient's leukemia to standard chemotherap y agents. In contrast, clonogenic cells from normal bone marrow formed colonies at near control numbers after exposure to much higher toxin concentrations (4 x 10(-9) mol/L) than those required to kill CFU-L fr om most patients, Thus, leukemic progenitors isolated directly from th e peripheral blood of most AML patients show the same sensitivity to D T388-GMCSF as previously demonstrated for AML cell lines. Under the sa me conditions of exposure, normal hematopoietic progenitors are relati vely unaffected by DT388-GMCSF, suggesting its potential as a therapeu tic agent in AML. (C) 1998 by The American Society of Hematology.