Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

Arthur E. Frankel, Michael Lilly, Robert Kreitman, Donna Hogge, Miloslav Beran, Melvin H. Freedman, Peter D. Emanuel, Chris McLain, Philip Hall, Edward Tagge, Marc Berger, Connie Eaves

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Abstract

We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM- CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM- CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic myelomonocytic leukemia (CMML) patients to 10-9 mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte- macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly 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 number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34+ bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor α and/or β chain's. These studies showed that high-affinity ligand binding was sufficient for DT388-GMCSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased 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 patients with these diseases.

Original languageEnglish (US)
Pages (from-to)4279-4286
Number of pages8
JournalBlood
Volume92
Issue number11
StatePublished - Dec 1 1998

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Juvenile Myelomonocytic Leukemia
Leukemia, Myelomonocytic, Chronic
Diphtheria Toxin
Poisons
Granulocyte-Macrophage Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Toxicity
Bearings (structural)
Fusion reactions
Cells
Signal transduction
Granulocyte-Macrophage Progenitor Cells
Macrophages
Proxy
Acute Myeloid Leukemia
Bone Marrow Cells
Signal Transduction
Bone
Leukemia
Stem Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. / Frankel, Arthur E.; Lilly, Michael; Kreitman, Robert; Hogge, Donna; Beran, Miloslav; Freedman, Melvin H.; Emanuel, Peter D.; McLain, Chris; Hall, Philip; Tagge, Edward; Berger, Marc; Eaves, Connie.

In: Blood, Vol. 92, No. 11, 01.12.1998, p. 4279-4286.

Research output: Contribution to journalArticle

Frankel, AE, Lilly, M, Kreitman, R, Hogge, D, Beran, M, Freedman, MH, Emanuel, PD, McLain, C, Hall, P, Tagge, E, Berger, M & Eaves, C 1998, 'Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia', Blood, vol. 92, no. 11, pp. 4279-4286.
Frankel, Arthur E. ; Lilly, Michael ; Kreitman, Robert ; Hogge, Donna ; Beran, Miloslav ; Freedman, Melvin H. ; Emanuel, Peter D. ; McLain, Chris ; Hall, Philip ; Tagge, Edward ; Berger, Marc ; Eaves, Connie. / Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. In: Blood. 1998 ; Vol. 92, No. 11. pp. 4279-4286.
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abstract = "We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM- CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM- CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71{\%}) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60{\%}) adult chronic myelomonocytic leukemia (CMML) patients to 10-9 mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte- macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly 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 number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34+ bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor α and/or β chain's. These studies showed that high-affinity ligand binding was sufficient for DT388-GMCSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased 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 patients with these diseases.",
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T1 - Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

AU - Frankel, Arthur E.

AU - Lilly, Michael

AU - Kreitman, Robert

AU - Hogge, Donna

AU - Beran, Miloslav

AU - Freedman, Melvin H.

AU - Emanuel, Peter D.

AU - McLain, Chris

AU - Hall, Philip

AU - Tagge, Edward

AU - Berger, Marc

AU - Eaves, Connie

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N2 - We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM- CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM- CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic myelomonocytic leukemia (CMML) patients to 10-9 mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte- macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly 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 number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34+ bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor α and/or β chain's. These studies showed that high-affinity ligand binding was sufficient for DT388-GMCSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased 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 patients with these diseases.

AB - We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM- CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM- CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic myelomonocytic leukemia (CMML) patients to 10-9 mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte- macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly 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 number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34+ bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor α and/or β chain's. These studies showed that high-affinity ligand binding was sufficient for DT388-GMCSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased 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 patients with these diseases.

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