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Gene Review

Mpl  -  myeloproliferative leukemia virus oncogene

Mus musculus

Synonyms: CD110, Myeloproliferative leukemia protein, Proto-oncogene c-Mpl, TPO-R, Thrombopoietin receptor, ...
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Disease relevance of Mpl


High impact information on Mpl


Chemical compound and disease context of Mpl


Biological context of Mpl

  • In this report, eight carboxyl truncations of the 121-aa murine Mpl cytoplasmic domain were tested for the ability to support growth of a cytokine-dependent cell line (Ba/F3) and for their capacity to induce TPO-stimulated tyrosine phosphorylation of specific signaling proteins [12].
  • Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl [13].
  • Furthermore, TPO-stimulated cellular proliferation appears to be directly correlated with receptor internalization, indicating that internalization of the TPO/Mpl complex may be essential for normal signal transduction [14].
  • These data help identify the receptor motifs involved in TPO-induced internalization of Mpl and suggest that Mpl translocation may be necessary for normal cellular proliferation [14].
  • Since the anti-FLAG antibodies do not react with the TPO binding site of the receptor, we hypothesize that they can trigger a distinct signal by dimerizing Mpl in a manner different from that induced by TPO [15].

Anatomical context of Mpl


Associations of Mpl with chemical compounds

  • A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl [20].
  • MATERIALS AND METHODS: Delta60-Mpl knockin mice, Stat5a(-/-)/b(-/-), Stat5a(-/-), and Stat5b(-/-) mice and wild-type (WT) controls were given a lethal myelosuppressive regimen: 80 mg/kg carboplatin intravenously followed by 7.5 or 6.5 Gy 137Cs total-body irradiation [21].
  • The SH2 domains of CIS1, constructed as glutathione S-transferase fusion protein, bound to activated Mpl in vitro [22].
  • Comparison of the platelet response to 5-FU in young (6-12 weeks) and old (33-46 weeks) c-mpl(-/-) mice found that older mice produced a much more marked response than younger mice, with a mean maximum platelet level of approximately 1700 x 10(9)/L [4].
  • Enforced expression of c-mpl in embryonic stem (ES) cells inactivated for this gene results in protein expression in all the ES cell progeny, producing cells that do not belong to the megakaryocytic lineage and are responsive to PEG-rhuMGDF, a truncated form of human thrombopoietin (TPO) conjugated to polyethylene glycol [23].

Physical interactions of Mpl

  • OBJECTIVE: Blood levels of thrombopoietin (TPO) are regulated in part by cellular degradation following its binding to the cell surface receptor c-mpl [24].

Regulatory relationships of Mpl

  • MATERIALS AND METHODS: A cassette coding for MplK cDNA was introduced into parental and MplP-expressing BaF3 cells and TPO-mediated cell growth studied [25].
  • OBJECTIVE: To determine the role of the c-terminal half of c-Mpl in Mpl-L-induced myeloprotection and the importance of Stat5 isoforms in the survival signaling pathways induced by Mpl ligand [21].
  • We have previously demonstrated that cyclin D3 is expressed in megakaryocytes and is induced upon treatment with Mpl ligand [26].
  • In response to literature reports of Mpl ligand-induced transient increases in p21Cip1/WAF1 mRNA in polyploidizing megakaryocytic cell lines, we have examined p21 transcript levels in both normal and transgenic megakaryocytes [26].
  • The Mpl-type SAGs induced more potent proliferation of Ba/F3 and cynomolgus CD34(+) cells than the GCR-type SAG [27].

Other interactions of Mpl

  • Thrombopoietin (TPO), the ligand for the receptor protooncogene c-mpl, has been cloned and shown to be the critical regulator of platelet production [28].
  • The activity of the c-mpl promoter in the presence of cotransfected GATA-1 was significantly increased compared with that of the control [16].
  • Cytokine production and function in c-mpl-deficient mice: no physiologic role for interleukin-3 in residual megakaryocyte and platelet production [29].
  • Functional regions of the mouse thrombopoietin receptor cytoplasmic domain: evidence for a critical region which is involved in differentiation and can be complemented by erythropoietin [30].
  • Furthermore, previous studies of the physical interaction between Mpl and the JAKs are extended, showing a difference in the association of JAK2 and TYK2 with the TPO receptor [31].

Analytical, diagnostic and therapeutic context of Mpl

  • Similarly, Western blot analysis of MKs produced in the presence or absence of TPO showed no difference in Mpl levels [32].
  • Thrombopoietin and the c-Mpl receptor: insights from gene targeting [33].
  • Genomic sequence analysis identified differential splicing of alternative exon 4 sequences as the likely basis for these transcripts, which are predicted to encode receptors which differ within the first Mpl hematopoietin receptor domain [34].
  • Engineering of cell lines expressing c-mpl provided a sensitive tool for detecting the ligand of Mpl, and led to the molecular cloning of TPO, the long sought proliferation and differentiation factor for the megakaryocytic lineage [35].
  • In serial transplantation experiments, STAT5ab(-/-) and c-Mpl(-/-) BM both failed to provide consistent engraftment in tertiary hosts and could not radioprotect lethally irradiated quaternary recipients [36].


  1. Thrombocytopenia in c-mpl-deficient mice. Gurney, A.L., Carver-Moore, K., de Sauvage, F.J., Moore, M.W. Science (1994) [Pubmed]
  2. Mutational analysis of thrombopoietin for identification of receptor and neutralizing antibody sites. Pearce, K.H., Potts, B.J., Presta, L.G., Bald, L.N., Fendly, B.M., Wells, J.A. J. Biol. Chem. (1997) [Pubmed]
  3. Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia. Ballmaier, M., Germeshausen, M., Krukemeier, S., Welte, K. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  4. Thrombocytopenic c-mpl(-/-) mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response. Levin, J., Cocault, L., Demerens, C., Challier, C., Pauchard, M., Caen, J., Souyri, M. Blood (2001) [Pubmed]
  5. Memorial lecture. Megakaryocytic growth factors: is there a new approach for management of thrombocytopenia in patients with malignancies? Hofmann, W.K., Ottmann, O.G., Hoelzer, D. Leukemia (1999) [Pubmed]
  6. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Bartley, T.D., Bogenberger, J., Hunt, P., Li, Y.S., Lu, H.S., Martin, F., Chang, M.S., Samal, B., Nichol, J.L., Swift, S. Cell (1994) [Pubmed]
  7. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Souyri, M., Vigon, I., Penciolelli, J.F., Heard, J.M., Tambourin, P., Wendling, F. Cell (1990) [Pubmed]
  8. cMpl ligand is a humoral regulator of megakaryocytopoiesis. Wendling, F., Maraskovsky, E., Debili, N., Florindo, C., Teepe, M., Titeux, M., Methia, N., Breton-Gorius, J., Cosman, D., Vainchenker, W. Nature (1994) [Pubmed]
  9. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. de Sauvage, F.J., Hass, P.E., Spencer, S.D., Malloy, B.E., Gurney, A.L., Spencer, S.A., Darbonne, W.C., Henzel, W.J., Wong, S.C., Kuang, W.J. Nature (1994) [Pubmed]
  10. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Lok, S., Kaushansky, K., Holly, R.D., Kuijper, J.L., Lofton-Day, C.E., Oort, P.J., Grant, F.J., Heipel, M.D., Burkhead, S.K., Kramer, J.M. Nature (1994) [Pubmed]
  11. Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Ulich, T.R., del Castillo, J., Yin, S., Swift, S., Padilla, D., Senaldi, G., Bennett, L., Shutter, J., Bogenberger, J., Sun, D. Blood (1995) [Pubmed]
  12. Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain. Drachman, J.G., Kaushansky, K. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  13. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Alexander, W.S., Roberts, A.W., Nicola, N.A., Li, R., Metcalf, D. Blood (1996) [Pubmed]
  14. Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic motifs. Dahlen, D.D., Broudy, V.C., Drachman, J.G. Blood (2003) [Pubmed]
  15. Differential signalling of NH2-terminal flag-labelled thrombopoietin receptor activated by TPO or anti-FLAG antibodies. Millot, G.A., Vainchenker, W., Duménil, D., Svinarchuk, F. Cell. Signal. (2004) [Pubmed]
  16. Forced GATA-1 expression in the murine myeloid cell line M1: induction of c-Mpl expression and megakaryocytic/erythroid differentiation. Yamaguchi, Y., Zon, L.I., Ackerman, S.J., Yamamoto, M., Suda, T. Blood (1998) [Pubmed]
  17. Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs. Xie, X., Chan, R.J., Johnson, S.A., Starr, M., McCarthy, J., Kapur, R., Yoder, M.C. Blood (2003) [Pubmed]
  18. Effects of megakaryocyte growth and development factor (thrombopoietin) on liver endothelial cells in vitro. Cardier, J.E. Microvasc. Res. (1999) [Pubmed]
  19. Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Kimura, S., Roberts, A.W., Metcalf, D., Alexander, W.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  20. A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl. Miyakawa, Y., Drachman, J.G., Gallis, B., Kaushansky, A., Kaushansky, K. J. Biol. Chem. (2000) [Pubmed]
  21. Differential role of Stat5 isoforms in effecting hematopoietic recovery induced by Mpl-ligand in lethally myelosuppressed mice. Pestina, T.I., Jackson, C.W. Exp. Hematol. (2003) [Pubmed]
  22. Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway. Okabe, S., Tauchi, T., Morita, H., Ohashi, H., Yoshimura, A., Ohyashiki, K. Exp. Hematol. (1999) [Pubmed]
  23. Requirement for mitogen-activated protein kinase activation in the response of embryonic stem cell-derived hematopoietic cells to thrombopoietin in vitro. Filippi, M.D., Porteu, F., Pesteur, F.L., Schiavon, V., Millot, G.A., Vainchenker, W., de Sauvage, F.J., Dubart Kupperschmitt, A., Sainteny, F. Blood (2002) [Pubmed]
  24. The Mpl receptor expressed on endothelial cells does not contribute significantly to the regulation of circulating thrombopoietin levels. Geddis, A.E., Fox, N.E., Kaushansky, K. Exp. Hematol. (2006) [Pubmed]
  25. MplK, a natural variant of the thrombopoietin receptor with a truncated cytoplasmic domain, binds thrombopoietin but does not interfere with thrombopoietin-mediated cell growth. Millot, G.A., Feger, F., Garçon, L., Vainchenker, W., Dumenil, D., Svinarchuk, F. Exp. Hematol. (2002) [Pubmed]
  26. Cyclin D3 and megakaryocyte development: exploration of a transgenic phenotype. Zimmet, J.M., Toselli, P., Ravid, K. Stem Cells (1998) [Pubmed]
  27. New selective amplifier genes containing c-Mpl for hematopoietic cell expansion. Nagashima, T., Ueda, Y., Hanazono, Y., Kume, A., Shibata, H., Ageyama, N., Terao, K., Ozawa, K., Hasegawa, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  28. Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. Kaushansky, K., Broudy, V.C., Grossmann, A., Humes, J., Lin, N., Ren, H.P., Bailey, M.C., Papayannopoulou, T., Forstrom, J.W., Sprugel, K.H. J. Clin. Invest. (1995) [Pubmed]
  29. Cytokine production and function in c-mpl-deficient mice: no physiologic role for interleukin-3 in residual megakaryocyte and platelet production. Gainsford, T., Roberts, A.W., Kimura, S., Metcalf, D., Dranoff, G., Mulligan, R.C., Begley, C.G., Robb, L., Alexander, W.S. Blood (1998) [Pubmed]
  30. Functional regions of the mouse thrombopoietin receptor cytoplasmic domain: evidence for a critical region which is involved in differentiation and can be complemented by erythropoietin. Porteu, F., Rouyez, M.C., Cocault, L., Bénit, L., Charon, M., Picard, F., Gisselbrecht, S., Souyri, M., Dusanter-Fourt, I. Mol. Cell. Biol. (1996) [Pubmed]
  31. Thrombopoietin signal transduction in purified murine megakaryocytes. Drachman, J.G., Sabath, D.F., Fox, N.E., Kaushansky, K. Blood (1997) [Pubmed]
  32. High-level expression of Mpl in platelets and megakaryocytes is independent of thrombopoietin. Cohen-Solal, K., Vitrat, N., Titeux, M., Vainchenker, W., Wendling, F. Blood (1999) [Pubmed]
  33. Thrombopoietin and the c-Mpl receptor: insights from gene targeting. Alexander, W.S. Int. J. Biochem. Cell Biol. (1999) [Pubmed]
  34. Structure and transcription of the genomic locus encoding murine c-Mpl, a receptor for thrombopoietin. Alexander, W.S., Dunn, A.R. Oncogene (1995) [Pubmed]
  35. Mpl: from an acute myeloproliferative virus to the isolation of the long sought thrombopoietin. Souyri, M. Semin. Hematol. (1998) [Pubmed]
  36. Hematopoietic-repopulating defects from STAT5-deficient bone marrow are not fully accounted for by loss of thrombopoietin responsiveness. Bradley, H.L., Couldrey, C., Bunting, K.D. Blood (2004) [Pubmed]
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