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Blood, 15 November 2001, Vol. 98, No. 10, pp. 3058-3065
NEOPLASIA
Expression of tumor necrosis factor-related apoptosis-inducing
ligand, Apo2L, and its receptors in myelodysplastic
syndrome: effects on in vitro hemopoiesis
Dae Young Zang,
Ray G. Goodwin,
Michael R. Loken,
Eileen Bryant, and
H. Joachim Deeg
From the Clinical Research Division, Fred Hutchinson
Cancer Research Center and the Department of Medicine, University of
Washington; Immunex; and Hematologics, Seattle, WA.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a
member of the tumor necrosis factor (TNF) family, binds to several
cell-surface receptors with distinct functions (agonistic receptors 1 and 2 [TRAIL-R1, TRAIL-R2]; decoy receptors 3 and 4 [TRAIL-R3,
TRAIL-R4]). Expression and function was characterized in patients with
myelodysplastic syndromes (MDSs). While normal marrow showed negligible
expression of TRAIL and receptors (except TRAIL-R3), TRAIL and all
receptors were constitutively expressed in MDS marrow. Following TRAIL
exposure, MDS marrow showed significant increases in apoptosis, whereas
normal marrow, except for a subset of CD34+ precursors, did
not (P = .012). Marrow from 21 patients with MDS was then
propagated in long-term cultures in the presence or absence of TRAIL.
While in advanced MDS (refractory anemia with excess blasts in
transformation [RAEB-T] and tAML [MDS transformed into
AML]), colony numbers decreased in the presence of TRAIL (63.0% ± 10.4% of untreated group [100%]), numbers
increased in patients with RA or RAEB (160.2% ± 90.5% of untreated
group). TRAIL eliminated preferentially clonally abnormal cells
as identified by chromosomal markers. Thus, TRAIL and receptor
expression differed significantly between normal and MDS marrow, and
TRAIL modulated in vitro hemopoiesis in MDS dependent upon disease
stage but not, to a detectable extent, in normal marrow.
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