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Flt3 ligand level reflects hematopoietic progenitor cell function in
aplastic anemia and chemotherapy-induced bone marrow aplasia
A Wodnar-Filipowicz, SD Lyman, A Gratwohl, A Tichelli, B Speck and C Nissen
Department of Research and Division of Hematology, University Hospital
Basel, Switzerland.
Flt3 ligand (flt3L) is a member of a small family of cytokines acting as
tyrosine kinase receptor ligands that stimulate the proliferation of
primitive hematopoietic progenitors in vitro. To gain insight into the
physiological role of flt3L in early hematopoiesis, levels of flt3L were
determined in serum of patients with multilineage bone marrow failure and
related to the severity of stem cell depletion. In patients with aplastic
anemia (AA) and in cancer patients with chemotherapy- induced transient
suppression of hematopoiesis, flt3L fluctuated in an inverse relationship
to the degree of bone marrow failure. In severe AA at diagnosis, levels of
circulating soluble flt3L were highly elevated (2,653 +/- 353 pg/mL) as
compared with normal blood serum values of 14 +/- 39 pg/mL. Flt3L returned
to near normal levels within the first 3 months following successful bone
marrow transplantation and in autologous remission induced by
immunosuppressive therapy with antilymphocyte globulin (ALG; 100 +/- 31 and
183 +/- 14 pg/mL, respectively). In contrast, rejection of the graft or
relapse of the disease after ALG was accompanied by an increase to high
pretreatment concentrations of the circulating cytokine (3,770 +/- 2,485
and 1,788 +/- 233 pg/mL, respectively). Flt3L in serum inversely correlated
with the colony-forming ability of AA bone marrow precursors in vitro (R =
- .86), indicating that the concentration of the ligand reflects
hematopoiesis at the progenitor cell level. Flt3L increased to 2,500 pg/mL
in the serum of leukemia patients during chemoradiotherapy- induced bone
marrow suppression and returned to normal values along with hematopoietic
recovery. Expression of the membrane-bound form of flt3L was significantly
elevated in mononuclear bone marrow and peripheral blood cells from
patients with severe pancytopenia, suggesting de novo synthesis of the
factor in response to bone marrow failure. The data provide a strong
argument for the involvement of flt3L in the regulation of early
hematopoiesis in vivo.
Volume 88,
Issue 12,
pp. 4493-4499,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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