Thrombopoietin (TPO) was the name proposed by Kelemen in 1958 for the hematopoietic growth factor (HGF) presumed to regulate platelet production like erythropoietin (EPO) regulates erythrocyte production (1,2). Despite almost 40 years of research efforts, TPO was finally purified in 1994 by five separate groups using several approaches. Two of the research groups purified the molecule directly from the plasma of thrombocytopenic mice (3) or sheep (4) using bioassays to detect the stimulation of megakaryocyte growth. The others purified TPO from thrombocytopenic animal plasma by affinity purification methods that used the previously described, presumed TPO receptor, c-mpl (5,6). Finally, one group subjected a BaF3 cell line containing the presumed TPO receptor, c-mpl, to mutagenesis and selected for clones exhibiting exogenous factor-independent autocrine growth (7).

Although all the molecules initially discovered had the same amino acid sequence, some groups called the molecule TPO and others called it megakaryocyte growth and

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

Table 1

The Thrombopoietins (c-mpl Ligands)

Endogenous thrombopoietin (TPO)

Recombinant human thrombopoietin (rHuTPO)

Pegylated human growth and development factor (PEG-rHuMGDF)

Promegapoietin (TPO/IL-3 fusion protein)

Thrombopoietin peptide mimetics

Thrombopoietin nonpeptide mimetics development factor (MGDF) (5), c-mpl ligand (6), or megapoietin (4). MGDF was the name given to the 25- and 31-kDa amino-terminal fragments of full-length TPO purified from thrombocytopenic canine plasma that stimulated an increase in the size and number of megakaryocyte colonies in vitro (8). Megapoietin was the name given the 31-kDa amino-terminal TPO fragment purified from thrombocytopenic sheep plasma based on its ability to stimulate an increase in the number and ploidy of megakary-ocytes in culture (4,9).

The name c-mpl ligand comes from the fact that before its identification as the TPO receptor, v-mpl was found to be a truncated hematopoietic cytokine receptor encoded by a murine retroviral oncogene that caused a myeloproliferative leukemia (hence the name "mpl") in mice (10). When the full-length cellular homolog c-mpl was cloned in 1992 (11), it was found to be present in megakaryocytes and platelets, and this led to the presumption, now known to be correct, that it was the TPO receptor. This information led many to attempt to find the ligand ("c-mpl ligand") that bound to the c-mpl receptor. In retrospect, it is now known that the c-mpl ligand is TPO and that c-mpl is the TPO receptor. The term "c-mpl ligand" is often used interchangeably with TPO, but it more appropriately describes a family of ligands that bind to c-mpl, including endogenous TPO, recombinant human TPO (rHuTPO), pegylated MGDF (PEG-rHuMGDF), promegapoietin (a fusion protein of interleukin [IL]-3 and TPO), and TPO mimetics (Table 1).

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