Flt3 ligand level reflects hematopoietic progenitor cell function in multilineage bone marrow failure

In order to get insight into the physiological role of fU3 ligand (flt3L) in early hematopoiesis, levels of this cytokine were determined in serum of patients with multilineage bone marrow failure and related to severity of the disease. In patients with aplastic anemia (AA) and in cancer patients with chemotherapy-induced transient suppression of hematopoiesis, fltSL fluctuated in an inverse relationship to the degree of hone marrow failure. In severe AA at diagnosis, fll3L levels were highly elevated to 2653±353 pg/ml as compared to normal values of 14±39 pg/ml measured by ELBA. Flt3L returned to near normal levels following successful bone marrow transplantation and in autotogous remission induced by immunosuppressive therapy. In contrary, rejection of the graft or relapse of AA were accompanied by increase to high pretreatment concentrations of the circulating ligand. One lineage-correction by transfusions or administration of G-CSF did not lower elevated flt3L in patients with severe AA. Transition to clonal disorders of hematopoiesis, PNH and MDS. was not heralded by any changes in flt3L level. FH3L in serum inversely correlated with the colony-forming ability of AA bone marrow precursors in vitro (R=-0.86), indicating that the concentration of the ligand reflects hematopoiesis at the progenitor cell level. In leukemia patients, flt3L in serum increased to 2500 pg/ml during chemotherapy-induced bone marrow suppression and returned to normal values along with hematopoietic recovery. In the period of pancytopenia, expression of the membrane-bound form of flt3L detected by FACS analysis on the surface of mononuclear cells, and levels of fU3L raRNA were significantly elevated, suggesting transcriptionai activation of fU3L gene and de novo synthesis of the ligand in response to stem cell depletion. Our results identify flt3L as the first early-acting hematopoietic cytokine shown to reflect the clinical evolution in primary and secondary bone marrow hypoplasia. Inverse correlation with severity of bone marrow failure is a strong argument for the involvement of flt3L in regulation of early hematopoiesis and suggest the existence of a feed-back mechanism at the stem/progenitor cell level which controls the production of flt3L .