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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1155-1164
PLENARY PAPER
Fas-L up-regulation by highly malignant myeloma plasma cells:
role in the pathogenesis of anemia and disease progression
Franco Silvestris,
Marco Tucci,
Paola Cafforio, and
Franco Dammacco
From the Department of Internal Medicine and
Oncology, Department of Biomedical Sciences and Human Oncology,
Section of Internal Medicine and Clinical Oncology, University of Bari,
Italy.
Highly malignant myeloma cells up-regulate their Fas-ligand (Fas-L)
to escape immune surveillance by Fas+ cytotoxic cells. Here
it is demonstrated that this abnormality is involved in the
pathogenesis of the severe anemia associated with progression of
multiple myeloma (MM). By measuring Fas and Fas-L in plasma cells and
erythroblasts from 19 MM patients and 5 with monoclonal gammopathies of
undetermined significance (MGUS), it was found that both
Fas-L+ myeloma cells and Fas+ erythroid
progenitors were significantly increased in patients with stage III MM
whose erythroblasts, cultured in the presence of autologous plasma
cells or their supernatant, underwent prompt apoptosis as evaluated by
propidium iodide staining, the TUNEL assay, and detection of the
APO2.7-reactive mitochondrial antigen. Flow cytometry of fresh
erythroblasts revealed a considerable expression of the caspases CPP32
and FLICE in both their constitutive proenzymatic forms and in cleaved
subunits. By contrast, their intracytoplasmic expression was defective
in patients with inactive disease and MGUS controls. The evidence that
Fas-L+ myeloma clones directly prime erythroblast
apoptosis in vivo was further supported by the occurrence of
fluorescein isothiocyanate-TUNEL+ erythroblasts
juxtaposed to myeloma cells in bone marrow smears. These results
strongly suggest that the deregulated apoptosis in myeloma clones plays
an active role in the progressive destruction of the erythroid matrix
by a cytotoxic mechanism based on up-regulation of Fas-L.
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