ABSTRACT. In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFalpha, M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNF\140 were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.

Keywords: Gaucher Disease, cytokines, macrophages, alglucerase, enzyme supplementation therapy.

Reprint requests to: Carla E.M. Hollak, M.D., Academic Medical Centre, University of Amsterdam, Department of Internal Medicine, F4-222, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands, phone: 20-5669111, fax: 20-6919743, e-mail: c.e.hollak@amc.uva.nl.

ABSTRACT. We present here the case of a Japanese female patient with aplastic anemia who developed monosomy 7 and clonal evolution following a treatment with recombinant human granulocyte colony- stimulating factor (rhG-CSF). At the onset of aplastic anemia, cytogenetic analysis was 46, XX and X-inactivation/methylation analysis revealed a polyclonal pattern. After 4 months of administration of rhG-CSF, she had 45, XX, -7 and a clonal pattern, although there were no morphological evidence of a myelodysplastic syndrome or leukemia. The ratio of monosomy 7 to normal analyzed by fluorescence in situ hybridization decreased after discontinuation of rhG-CSF and there were still no dysplastic changes and/or increased numbers of blasts. These results indicate that the acquisition of monosomy 7 following rhG-CSF treatment dose not always cause clonal evolution to induce hematological malignancies.

Keywords: Aplastic anemia, rhG-CSF, monosomy 7, clonality, X- inactivation, leukemogenesis.

Reprint requests to: Hiroshi Mohri, M.D., The First Department of Internal Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236, Japan, phone: 45-787-26630, fax: 45-786-3444, e-mail: mohrih@yellow.med.yokohama-cu.ac.jp.