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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4279-4286
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, and
Connie Eaves
From the Wake Forest Comprehensive Cancer Center/Bowman Gray School
of Medicine, Winston-Salem, NC; the Division of Medical Oncology, the
Department of Medicine, University of Washington, Seattle; Laboratory
of Molecular Biology, National Cancer Institute, National Institutes of
Health (NIH), Bethesda, MD; Terry Fox Laboratory, British Columbia
Cancer Agency, Vancouver, BC, Canada; the Leukemia Department,
University of Texas M.D. Anderson Cancer Center, Houston; the Division
of Haematology/Oncology, The Hospital for Sick Children, Toronto,
Ontario, Canada; Comprehensive Cancer Center, University of Alabama at
Birmingham; and the Departments of Surgery and Pharmaceutical Sciences,
Medical University of South Carolina, Charleston.
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  and/or  chains. These studies showed that
high-affinity ligand binding was sufficient for DT388-GM-CSF-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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