DIPHTHERIA-TOXIN FUSED TO GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IS TOXIC TO BLASTS FROM PATIENTS WITH JUVENILE MYELOMONOCYTIC LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA

We have previously demonstrated that human granulocyte-macrophage colo ny-stimulating factor fused to a truncated diphtheria toxin (DT388-GM- CSF) is toxic to patient acute myeloid leukemia progenitors bearing th e GM-CSF receptor, but not normal marrow progenitors. We now report th at exposure of mononuclear cells from five of seven (71%) juvenile mye lomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chr onic myelomonocytic leukemia (CMML) patients to 10(-9) mol/L DT388-GM- CSF for 48 hours in culture reduces the number of cells capable of for ming colonies in semisolid medium (colony-forming units-leukemia) 10-f old to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid p rogenitors (colony-forming unit-granulocyte-macrophage) from six diffe rent donors treated and assayed under identical conditions were consis tently insensitive to the same fusion toxin even when treated as highl y purified CD34(+) cells. The leukemic progenitors from the two other JMML patients showed intermediate sensitivity to DT388-GM-CSF and the leukemic progenitors from eight of the 20 (40%) CMML patients were not different from normal progenitors. Parallel measurements of the numbe r and affinity of GM-CSF receptors on cells from the same samples show ed no consistent differences between JMML, CMML, and normal light dens ity or CD34+ bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fu sion toxin is therefore not likely to be explained by an increased den sity of GM-CSF receptors on these cells. We also examined the DT388-GM -CSF sensitivity of two murine cell lines transfected with cDNAs encod ing varying portions of the human GM-CSF receptor or and/or beta chain s. These studies showed that high-affinity ligand binding was sufficie nt for DT388-GM-CSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of t he host cell had a major influence on the degree to which this decreas ed the toxicity of DT388-GM-CSF. The selective sensitivity to DT388-GM -CSF of leukemic progenitors from a majority of JMML and CMML patients suggests that this agent could have therapeutic potential for some pa tients with these diseases; (C) 1998 by The American Society of Hemato logy.