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.
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.
White
S M
SM
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Alarcon
M H
MH
Tweardy
D J
DJ
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection
D020033:Protein Isoforms; D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor