LOW-LEVELS OF ERYTHROID AND MYELOID PROGENITORS IN THROMBOPOIETIN-DEFICIENT AND C-MPL-DEFICIENT MICE

Thrombopoietin (TPO), the ligand for the c-mpl receptor, has been show n to be the major regulator of platelet production. Mice deficient in either c-mpl or TPO generated by homologous recombination show a drama tic decrease in platelet counts, but other blood cell counts are norma l. Because TPO treatment of myelosuppressed mice not only enhances the recovery of platelets but also accelerates erythroid recovery, we inv estigated the levels of myeloid and erythroid progenitor cells in TPO- or c-mpl-deficient mice. Our results show that the number of megakary ocyte, granulocyte-macrophage, erythroid, and multilineage progenitors are significantly reduced in the bone marrow, spleen, and peripheral blood of either TPO- or c-mpl-deficient mice. Administration of recomb inant murine TPO to TPO-deficient mice and control littermate mice sig nificantly increased the absolute number of myeloid, erythroid, and mi xed progenitors in bone marrow and spleen. This increase was especiall y apparent in TPO-deficient mice where numbers were increased to a lev el greater than in diluent-treated control mice and approached or equa led that in the TPO-treated control mice. Moreover, TPO-administration greatly increased the number of circulating progenitors as well as pl atelets in both TPO-deficient and control mice. Furthermore, the megak aryocytopoietic activity of other cytokines in the absence of a functi onal TPO or c-mpl gene was shown both in vitro and in vivo. (C) 1996 b y The American Society of Hematology.