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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3335-3340
Inhibition of granulocyte colony-stimulating
factor-mediated myeloid maturation by low level expression of the
differentiation-defective class IV granulocyte colony-stimulating
factor receptor isoform
Scott M. White,
Mark H. Alarcon, and
David J. Tweardy
From the Division of Infectious Diseases, Department of Medicine,
University of Pittsburgh School of Medicine, Pittsburgh, PA, and the
Section of Infectious Diseases, Department of Medicine, Baylor College
of Medicine, Houston, TX.
In acute myeloid leukemia (AML), granulocyte colony-stimulating
factor receptor (G-CSFR) proliferative and maturational signaling pathways are uncoupled. Seven human G-CSFR mRNA isoforms exist, named
class I through class VII. The 183-amino acid cytosolic domain of the
class I isoform provides all signaling activities. The class IV isoform
is "differentiation defective" because the carboxy-terminal 87 amino acids are replaced with 34 amino acids of novel sequence. In more
than 50% of AML samples, the class IV/class I G-CSFR mRNA ratio is
aberrantly elevated compared to normal CD34+ bone marrow
cells. We hypothesized that the increased relative expression of class
IV G-CSFR in AML uncouples proliferative and maturational G-CSFR
signaling pathways. To test this, we transfected the G-CSF-responsive
murine cell line 32Dcl3 with class IV G-CSFR cDNA. After 10 days of
G-CSF stimulation, clones expressing class IV G-CSFR had greater
percentages of myeloblasts and promyelocytes than controls
(53% ± 13% versus 3% ± 2%). Differential counts over time
demonstrated delayed G-CSF-driven maturation in 5 class IV-expressing
clones, with 2 clones demonstrating a subpopulation that completely
failed to differentiate. Heterologous class IV expression did not
affect G-CSF-dependent proliferation. Class IV/murine G-CSFR mRNA
ratios after 24 hours of G-CSF stimulation for 3 of the 5 clones
(range, 0.090 to 0.245; mean, 0.152 ± 0.055) are within the range
of class IV/class I mRNA ratios seen in patients with AML. This
indicates that aberrantly increased relative class IV G-CSFR expression
seen in AML can uncouple G-CSFR proliferative and maturational
signaling pathways.
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