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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1305-1313
NEOPLASIA
Negative regulation of erythroblast maturation by
Fas-L+/TRAIL+ highly malignant plasma cells: a
major pathogenetic mechanism of anemia in multiple myeloma
Franco Silvestris,
Paola Cafforio,
Marco Tucci, and
Franco Dammacco
From DIMO, Department of Biomedical Sciences and Human
Oncology, Section of Internal Medicine and Clinical Oncology,
University of Bari, Italy.
Multiple myeloma (MM) is associated with severe
normochromic/normocytic anemia. This study demonstrates that the
abnormal up-regulation of apoptogenic receptors, including both Fas
ligand (L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), by highly malignant myeloma cells is involved in the pathogenesis of the ineffective erythropoiesis and chronic exhaustion of the erythroid matrix. By measuring Fas-L and TRAIL in plasma cells
and the content of glycophorin A (GpA) in erythroblasts from a cohort
of 28 untreated, newly diagnosed patients with MM and 7 with monoclonal
gammopathy of undetermined significance (MGUS), selected in relation to
their peripheral hemoglobin values, results showed that both
receptors occurred at high levels in 15 severely anemic MM
patients. Their marrow erythropoietic component was low and
included predominantly immature
GpA+dim erythroblasts, in
contrast with the higher relative numbers of mature
GpA+bright erythroid cells observed in the nonanemic
patients and those with MGUS. In cocultures with autologous
Fas-L+/TRAIL+ myeloma cells, the expanded
GpA+dim erythroid population
underwent prompt apoptosis after direct exposure to malignant plasma
cells, whereas erythroblasts from nonanemic patients were scarcely
affected. The evidence that Fas-L+/TRAIL+
malignant plasma cells prime erythroblast apoptosis by direct cytotoxicity was also supported by the increase of FLICE in fresh immature GpA+dim erythroid cells, whereas ICE and
caspase-10 increased in subsequent maturative forms. In addition,
GATA-1, a survival factor for erythroid precursors, was
remarkably down-regulated in fresh erythroblasts from the severely
anemic patients. These results indicate that progressive destruction of
the erythroid matrix in aggressive MM is due to cytotoxic mechanisms
based on the up-regulation in myeloma cells of Fas-L, TRAIL, or both.
It is conceivable that the altered regulation of these receptors
defines a peculiar cytotoxic phenotype that drives the progression of
aggressive MM.
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