Role forC-MPLand its Ligand Thrombopoietin in Early Hematopoiesis

Abstract

Proto-oncogene c-mpl is structurally homologous with the hematopoietic growth factor receptor superfamily. The ligand for c-mpl was purified and its gene cloned. Extensive functional studies revealed that the ligand for c-mpl plays a crucial role in megakaryocytopoiesis and platelet production, hence, this ligand proved to be the long-sought hematopoietin, thrombopoietin (TPO). We briefly review here the role for TPO in early hematopoiesis, based on our in vitro data obtained using a serum-free culture system. TPO in combination with the ligand for c-kit (SF) or interleukin-3 (IL-3) but not TPO alone supported the growth of murine primitive hematopoietic progenitors. Studies on lineage expression indicated that the progenitors supported by TPO plus SF or TPO plus IL-3 are multipotential. Delayed addition experiments demonstrated that TPO has the potential to effectively support the survival of primitive hematopoietic progenitors. TPO also hastened IL-3-dependent growth of progenitors by shortening the time required for cell-cycling. While size of the colonies did not differ between colonies supported by IL-3 alone and those supported by IL-3 plus TPO, the incidence of megakaryocyte-containing colonies in cultures supported by IL-3 plus TPO was higher than that in cultures supported by IL-3 alone. Taken together, TPO as a single factor can support the survival of hematopoietic progenitors and TPO synergizes with SF or IL-3 to be active on early multipotential hematopoietic progenitors. These findings suggest that the function of TPO initially thought to be restricted to the megakaryocytic lineage proved to be greater in hematopoiesis. Reports from other laboratories regarding the involvement of TPO in early hematopoiesis are also discussed.

Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor ( c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)

“…Together with receptors for erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), growth hormone (GH), and prolactin, c-mpl constitutes a subgroup of this superfamily, which characteristically forms homodimers following ligand binding (Elberg et al 1990;Fukunaga et al 1990;Cunningham et al 1991;Fuh et al 1992;Hooper et al 1993). c-mpl alterations could be related to the aplastic anemia often observed in CAMT without physical anomalies, as suggested by in vitro studies indicating that c-mpl and TPO may support the survival of hematopoietic progenitors, and that TPO acts in synergy with Stem Cell Factor (SCF) or Interleukin-3 (IL-3) on early multipotential hematopoietic progenitors (Katayama et al 1997;Kaushansky 1998a;Solar et al 1998). In animals, a deficiency of the c-mpl gene results in amegakaryocytic thrombocytopenia, decreased numbers of hematopoietic progenitors, and increased concentrations of circulating TPO in the absence of physical or developmental abnormalities (Gurney et al 1994;Alexander et al 1996a;Carver-Moore et al 1996;Kimura et al 1998).…”

“…Recent, in vitro studies indicate that c-mpl and TPO also play a role in early hematopoiesis. In particular, TPO supports the survival of hematopoietic progenitors and is active on early multipotential hematopoietic progenitors (Katayama et al 1997;Kaushansky 1998a;Solar et al 1998). In animals, a deficiency of the c-mpl gene results in amegakaryocytic thrombocytopenia, decreased numbers of hematopoietic progenitors, and increased concentrations of circulating TPO in the absence of physical or developmental abnormalities (Gurney et al 1994;Alexander et al 1996a;Carver-Moore et al 1996;Kimura et al 1998).…”

ITR‑284 modulates cell differentiation in human chronic myelogenous leukemia K562 cells

“…(c-MPL, TPO receptor) plays a crucial role in the differentiation of megakaryocytes and platelets (36)(37)(38). To determine whether ITR-284 and ATRA are involved in megakaryocyte differentiation, we treated K562 cells with either ITR-284 or ATRA for 24 h and examined the mRNA expression levels of GATA-2 and c-MPL by quantitative RT-PCR.…”

Expression of thrombopoietin receptor and its functional role in human B-precursor leukemia cells with 11q23 translocation or Philadelphia chromosome

“…[7][8][9][10] Several lines of the in vitro and in vivo evidence, however, revealed that TPO plays an important physiological roles in regulating early hematopoiesis by itself [11][12][13] or in synergy with other hematopoietic growth factors. [14][15][16][17][18][19] A number of studies have suggested that dysregulated expression of hematopoietic growth factors and/or their receptors could be involved in excessive proliferation and aberrant differentiation of leukemia cells. [20][21][22][23][24] It has been shown that c-mpl is detected by Northern blot (NB) analysis in a half of the patient samples of acute myeloblastic leukemia (AML) and myelodysplastic syndrome (MDS), and the TPO/c-Mpl interaction is implicated in the proliferation or megakaryocytic differentiation of the myeloblasts in some cases.…”