Synergistic interactions between recombinant human interleukin-3, GM-CSF and G-CSF in normal human marrow granulocyte-macrophage colony formation

Anemia and neutropenia are common complications of HIV infection. Antiretroviral therapy with zidovudine exacerbates bone marrow suppression by inhibiting proliferation of blood cell progenitor cells. In addition, treatment for opportunistic infections or malignancies can involve the use of myelosuppressive drugs. As a consequence, severe anemia and neutropenia can result, thereby limiting the utilization of antiretroviral drugs. Since antiretroviral therapy can increase survival, drugs that ameliorate myelosuppression are important adjuncts in the treatment of HIV-infected patients. Three hematopoietic growth factors are effective in the treatment of anemia or neutropenia. In four placebo-controlled trials, erythropoietin (EPO) at doses up to 600 U/kg/wk decreased mean transfusion requirements by 37%, increased mean hematocrit by 4.5% and corrected anemia in the majority of patients receiving zidovudine over a 12-week period. In a separate study, granulocyte colony-stimulating factor (G-CSF) corrected leukopenia and isolated neutrophil defects in 22 patients with AIDS without altering HIV expression. When erythropoietin was added to the regimen, combined G-CSF and EPO corrected both anemia and leukopenia and lessened subsequent zidovudine toxicity. Similarly, granulocyte macrophage-colony-stimulating factor (GM-CSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In controlled and uncontrolled trials, GM-CSF also appears to reduce toxicity from zidovudine, ganciclovir, and antineoplastic therapy. New combinations of hematopoietic stimulants are being used to decrease the toxicity from combination antiretroviral therapy with alpha interferon and cytotoxic chemotherapy in the treatment of AIDS-related malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)

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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

White

Alarcon

Tweardy³

2000

Blood

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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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Synergistic interactions between recombinant human interleukin-3, GM-CSF and G-CSF in normal human marrow granulocyte-macrophage colony formation

Cited by 5 publications

References 9 publications

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Hematopoietic Growth Factors as Adjuncts to Antiretroviral Therapy

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

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