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Diphtheria Toxin Fused to Granulocyte-Macrophage Colony-Stimulating Factor Eliminates Acute Myeloid Leukemia Cells With the Potential to Initiate Leukemia in Immunodeficient Mice, But Spares Normal Hemopoietic Stem Cells
Wim Terpstra,
Henk Rozemuller,
Dimitri A. Breems,
Elwin J.C. Rombouts,
Arie Prins,
David J.P. FitzGerald,
Robert J. Kreitman,
Jenne J. Wielenga,
Rob E. Ploemacher,
Bob Löwenberg,
Anton Hagenbeek, and
Anton C.M. Martens
From Institute of Hematology, Erasmus University, Rotterdam; Dr. Daniël den Hoed Cancer Center, Rotterdam, The Netherlands; and Laboratory of Molecular Biology, DCBDC, National Cancer Institute, Bethesda, MD.
We studied the cell kill induced by granulocyte-macrophage colony-stimulating factor (GM-CSF ) fused to Diphtheria Toxin (DT-GM-CSF ) in acute myeloid leukemia (AML) samples and in populations of normal primitive hemopoietic progenitor cells. AML samples from three patients were incubated in vitro with 100 ng/mL DT-GM-CSF for 48 hours, and AML cell kill was determined in a proliferation assay, a clonogenic assay colony-forming unit-AML (CFU-AML) and a quantitative long-term bone marrow (BM) culture ie, the leukemic-cobblestone area forming cell assay (L-CAFC). To measure an effect on cells with in vivo leukemia initiating potential DT-GM-CSF exposed AML cells were transplanted into immunodeficient mice. In two out of three samples it was shown that all AML subsets, including those with long-term abilities in vivo (severe combined immunodeficient mice) and in vitro (L-CAFC assay) were reduced in number by DT-GM-CSF. Cell kill induced by DT-GM-CSF could be prevented by coincubation with an excess of GM-CSF, demonstrating that sensitivity to DT-GM-CSF is specifically mediated by the GM-CSF receptor. Therefore, binding and internalization of GM-CSF probably occur in immature AML precursors of these two cases of AML. The third AML sample was not responsive to either GM-CSF or DT-GM-CSF. The number of committed progenitors of normal bone marrow (burst-forming unit-erythroid, colony-forming unit granulocyte- macrophage, and cobble stone area forming cell [CAFC] week 2) and also the number of cells with long-term repopulating ability, assayed as week 6 CAFC, were unchanged after exposure to DT-GM-CSF (100 ng/mL, 48 hours). These studies show that DT-GM-CSF may be used to eliminate myeloid leukemic cells with long-term potential in vitro and in immunodeficient mice, whereas normal hemopoietic stem cells are spared.
Blood, Vol. 90 No. 9 (November 1), 1997:
pp. 3735-3742
© 1997 by The American Society of Hematology.
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