Blood, 1 March 2001, Vol. 97, No. 5, pp. 1153-1153
Multiple myeloma: multiple ways to defeat erythropoiesis
Multiple myeloma (MM) accounts for 1% of all cancer deaths and
often is first suspected in an otherwise asymptomatic patient with
anemia. About two-thirds of patients with newly diagnosed MM are
anemic, and nearly all will eventually develop anemia during the course
of their disease. The cause of anemia in MM is often multifactorial,
including (1) massive marrow invasion by myeloma cells, (2)
erythropoietin deficiency, either an absolute deficiency due to overt
renal failure or relative deficiency despite apparently normal
kidney function, (3) treatment-induced myelosuppression or
myelodysplasia, (4) autoimmune hemolysis, (5) hemodilution, (6) high
marrow levels of IL-6 that can suppresses erythropoiesis, and (7) the
many usual causes of anemia in individuals of the same demographics as
myeloma patients.
The work by Silvestris et al (page 1155) points to yet another
mechanism of anemia in MM, one in which Fas ligand (Fas-L) expressed on
the surface of myeloma cells triggers programmed cell death of
Fas-expressing erythroid progenitors. Myeloma cells, like several
other malignant and some normal cells, express Fas-L as a mechanism to
escape immune surveillance by Fas bearing T-lymphocytes (Hahne et al,
Science 1996;274:1363-1366; Saas et al, J Clin Invest 1997;99:1173-1178). Silvestris et al convincingly demonstrate that
erythroid precursors contain the apoptotic machinery necessary to
respond to Fas-L and undergo apoptosis both in vitro and in vivo in the
presence of myeloma cells. Moreover, they correlate the expression of
Fas-L with progressive myeloma, which might help explain why
erythropoietin administration often relieves the anemia early in the
course of disease but is less effective in end-stage myeloma. Finally,
these results bring the anemia of myeloma into closer association with
that of the anemia of chronic inflammation and aplastic anemia, where
apoptotic responses to IFN-
appear to play a major pathogenic role
(Dai et al, Blood 1998;91:1235-1242; Young and Maciejewski, N Engl
J Med 1997;336:1365-1372).
Recognizing that Fas-L is at least in part responsible for anemia in
advanced stage myeloma might have therapeutic implications. Multiple
malignant and normal cell types express decoy Fas receptors (Pitti et
al, Nature 1998;396:699-703; Ohshima et al, Cancer Lett 2000;160:89-97;
Jenkins et al, J Biol Chem 2000;275:7988-7993), which by virtue of
alterations in the cytoplasmic signaling domain prevent Fas-L-induced
apoptosis. It is not a very far leap to envision that the
administration of a soluble form of Fas might be able to prevent the
suppression of erythropoiesis seen in aggressive multiple myeloma. One
need only turn to the success of soluble TNF receptors to find proof of
this principle.
Kenneth Kaushansky
University of Washington School of Medicine
