title: Flt3 ligand level reflects hematopoietic progenitor cell function in aplastic anemia and chemotherapy-induced bone marrow aplasia.
abstract: 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.
authors.affiliation: Department of Research and Division of Hematology, University Hospital Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Wodnar-Filipowicz
authors.forename: S D
authors.initials: SD
authors.lastname: Lyman
authors.forename: A
authors.initials: A
authors.lastname: Gratwohl
authors.forename: A
authors.initials: A
authors.lastname: Tichelli
authors.forename: B
authors.initials: B
authors.lastname: Speck
authors.forename: C
authors.initials: C
authors.lastname: Nissen
mesh_terms: D000741:Anemia, Aplastic / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D001853:Bone Marrow / Q000002:abnormalities*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D064420:Drug-Related Side Effects and Adverse Reactions; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy / Q000532:radiotherapy; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000097:blood / Q000378:metabolism*; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3