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 carboxyterminal 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 control (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 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 end maturational signaling pathways, (Blood, 2000; 95:3335-3340) (C) 2000 by The American Society of Hematology.