Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin

Abstract

The development of blood cells including expansion of megakaryocyte progenitor cells requires the interplay of marrow stromal cells and polypeptide cytokines. Recently, characterization of c-Mpl, the receptor encoded by the proto-oncogene c-mpl, revealed structural homology with the haematopoietic cytokine receptor family, and its involvement in megakaryocyte development. We report here that the ligand for c-Mpl is relatively lineage specific, works both alone and synergistically with early acting cytokines to support megakaryocyte colony formation, and acts at a late stage of development to increase megakaryocyte size, polyploidization and expression of differentiation markers. In vivo, c-Mpl ligand stimulates platelet production by greatly expanding marrow and splenic megakaryocytes and their progenitors, and by shifting the distribution of megakaryocyte ploidy to higher values. Thus, as c-Mpl ligand has the expected characteristics of the major regulator of megakaryocyte development, we propose that it be termed thrombopoietin.

Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro

“…Recently, several groups [2][3][4][5] cloned the ligand for the c-Mpl proto-oncogene [6] which is a member of the cytokine receptor superfamily. These studies and others have demonstrated that c-Mpl ligand plays a critical role in megakaryocytopoiesis and thrombopoiesis both in vitro and in vivo [2][3][4][5][7][8][9][10]. Therefore, c-Mpl ligand has been termed thrombopoietin (TPO) [3,7,8] or megakaryocyte growth and development factor (MGDF) [4].…”

“…These studies and others have demonstrated that c-Mpl ligand plays a critical role in megakaryocytopoiesis and thrombopoiesis both in vitro and in vivo [2][3][4][5][7][8][9][10]. Therefore, c-Mpl ligand has been termed thrombopoietin (TPO) [3,7,8] or megakaryocyte growth and development factor (MGDF) [4]. The cytokine receptor superfamily, which lacks a tyrosine kinase domain, couples ligand binding with the induction of protein-tyrosine phosphorylation that is essential for cytokine signaling [11].…”

Megakaryocyte growth and development factor (MGDF)-induced acute leukemia cell proliferation and clonal growth is associated with functional c-mpl

“…[16][17][18] In normal hematopoiesis MGDF acts as a growth factor for megakaryocytopoiesis. [19][20][21][22][23][24][25][26][27][28][29][30] In addition, recent reports demonDiscussion strate that c-mpl ligand can also enhance the proliferation of early erythroid progenitors. 53,54 Indeed, c-mpl is a member of Although leukemic progenitor cells apparently have escaped normal regulation by stimulatory or inhibitory factors in vivo, the cytokine receptor superfamily, with extensive aminoacid homologies to the receptors for erythropoietin, GM-CSF and clonogenic leukemic precursor cell growth in vitro of primary leukemias has been shown to be dependent on hematopoietic IL-3.…”

“…53,54 Indeed, c-mpl is a member of Although leukemic progenitor cells apparently have escaped normal regulation by stimulatory or inhibitory factors in vivo, the cytokine receptor superfamily, with extensive aminoacid homologies to the receptors for erythropoietin, GM-CSF and clonogenic leukemic precursor cell growth in vitro of primary leukemias has been shown to be dependent on hematopoietic IL-3. [19][20][21][22][23][24][25][26][27][28][29][30] Moreover, it has been demonstrated that human CD34 + CD38 − cells express c-mpl. The expression of c-mpl factors in most cases.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] liferation, demonstrate that MGDF induces tyrosine phos-A novel protein, the c-mpl ligand (TPO), has been recently phorylation of a 90 kDa protein(s) in MGDF responsive cells identified and cloned. [19][20][21][22][23][24] This cytokine binds to the c-mpl but not in unresponsive ones. In addition, in one responsive receptor and stimulates megakaryocyte proliferation and case co-immunoprecipitation studies demonstrate that the maturation in vitro and in vivo.…”