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MPL  -  myeloproliferative leukemia virus oncogene

Homo sapiens

 
 
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Disease relevance of MPL

 

High impact information on MPL

  • We show that in vitro infection of bone marrow cells with helper-free MPLV readily yields immortalized factor-independent hematopoietic cell lines of different lineages [4].
  • By sequencing the envelope gene of a biologically active MPLV clone, we found that this region comprises a novel oncogene named v-mpl in phase with two parts of the Friend murine leukemia virus envelope gene [4].
  • For R32NS1(81) MPL/CWS is superior to aluminum hydroxide as an adjuvant, and the data support the evaluation of this complex as an adjuvant for other vaccines [5].
  • Antibody responses to a Plasmodium falciparum circumsporozoite (CS) protein vaccine, R32NS1(81), administered with an adjuvant containing cell-wall skeleton of mycobacteria and monophosphoryl lipid A in squalane (MPL/CWS) have been compared to responses to the same immunogen administered with aluminum hydroxide [5].
  • Of the novel compounds recently evaluated in human trials, immunostimulatory molecules such as the lipopolysaccharide derived MPL and the saponin derivative QS21 appear most promising, although doubts have been raised as to their safety in humans [6].
 

Chemical compound and disease context of MPL

  • The lectins included galactophilic ones from Aplysia gonad, Erythrina corallodendron, Maclura pomifera (MPL), peanut, and Pseudomonas aeruginosa (PA-IL); fucose-binding lectins from Pseudomonas aeruginosa (PA-IIL), Ralstonia solanacearum (RSL), and Ulex europaeus (UEA-I), and mannose/glucose-binding Con A [7].
  • We conclude that the simple addition of MPL to the L2E7 fusion protein already adsorbed onto Alhydrogel preferentially enhances antigen specific in vitro T-cell proliferative responses, IFN gamma production and in vivo delayed type hypersensitivity responses without increasing its reactogenicity [8].
  • Laboratory studies revealed a positive ANA (1:2560 titer), positive antiphospholipid antibodies (GPL and MPL), circulating lupus anticoagulant, and depressed C3 and C4 [9].
  • MPL (Corixa) adjuvant is a chemically modified derivative of lipopolysaccharide that displays greatly reduced toxicity while maintaining most of the immunostimulatory activity of lipopolysaccharide [10].
 

Biological context of MPL

 

Anatomical context of MPL

 

Associations of MPL with chemical compounds

  • Because the action of TPO is not restricted to the megakaryocytic lineage, we studied the occurrence of TPO receptor mRNA and protein, and effects of TPO on cytosolic Ca(2+) levels and DNA synthesis in human umbilical vein endothelial cell cultures (HUVECs) [19].
  • We demonstrated that MPL adsorbed onto aluminium salt retains its capacity to activate an innate immune response as assessed by the production of TNFalpha by human monocytes (U937) [20].
  • Such an adjuvant is 3-deacylated monophosphoryl lipid A (MPL adjuvant, Corixa) [21].
  • METHODS: A multicentre, placebo-controlled, randomized, double-blind clinical study was performed with a new standardized allergy vaccine comprising a tyrosine-adsorbed glutaraldehyde-modified grass pollen extract containing MPL adjuvant [21].
  • They also reacted well with Wistaria floribunda (WFA), Glycine max (soybean, SBA), and Ricinus communis agglutinins and precipitated over 78% of the lectin nitrogen added, but reacted poorly or weakly with all alpha-anomeric GalNAc specific lectins, such as Helix pomatia (HPA), Phaseolus lunatus (lima bean, LBL), and Maclura pomifera (MPL) lectins [22].
 

Physical interactions of MPL

  • GATA-1 binds with low affinity to a unique GATA motif at -70 in the MPL promoter, and destruction of this site yields only a modest decrease in expression level in HEL cells [23].
 

Regulatory relationships of MPL

 

Other interactions of MPL

  • Altogether, our results are in line with a model in which binding of TPO to the TPO receptor (mpl) could activate the rapamycin-sensitive PI3K-AKT-mTOR-p70S6K pathway and its downstream targets in promoting megakaryocytic cell polyploidization [26].
  • We investigated the signals sent by the MPL cytoplasmic domain in fetal liver hematopoietic progenitors and during embryonic stem (ES) cell hematopoietic commitment [27].
  • Furthermore, GATA-1 and two Ets proteins, Ets-1 and Fli-1, can trans-activate the MPL promoter in heterologous cells [23].
  • The treatment of AML cells with rhTPO resulted in rapid tyrosine phosphorylation of the TPO-receptor, c-mpl, and STAT3 in all of cases tested [28].
  • In familial disorders, pathological mutations have been identified in some, but by no means all, cases: EPO receptor mutations in PFCP, TPO mutations in FT and, conversely, TPO receptor (c-mpl) mutations in CAMT [29].
 

Analytical, diagnostic and therapeutic context of MPL

References

  1. MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia. Pikman, Y., Lee, B.H., Mercher, T., McDowell, E., Ebert, B.L., Gozo, M., Cuker, A., Wernig, G., Moore, S., Galinsky, I., Deangelo, D.J., Clark, J.J., Lee, S.J., Golub, T.R., Wadleigh, M., Gilliland, D.G., Levine, R.L. PLoS Med. (2006) [Pubmed]
  2. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Vigon, I., Mornon, J.P., Cocault, L., Mitjavila, M.T., Tambourin, P., Gisselbrecht, S., Souyri, M. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  3. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Ding, J., Komatsu, H., Wakita, A., Kato-Uranishi, M., Ito, M., Satoh, A., Tsuboi, K., Nitta, M., Miyazaki, H., Iida, S., Ueda, R. Blood (2004) [Pubmed]
  4. 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]
  5. Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid A, and squalane in malaria circumsporozoite protein vaccine. Rickman, L.S., Gordon, D.M., Wistar, R., Krzych, U., Gross, M., Hollingdale, M.R., Egan, J.E., Chulay, J.D., Hoffman, S.L. Lancet (1991) [Pubmed]
  6. Advances in vaccine adjuvants. Singh, M., O'Hagan, D. Nat. Biotechnol. (1999) [Pubmed]
  7. Differential staining of Western blots of human secreted glycoproteins from serum, milk, saliva, and seminal fluid using lectins displaying diverse sugar specificities. Gilboa-Garber, N., Lerrer, B., Lesman-Movshovich, E., Dgani, O. Electrophoresis (2005) [Pubmed]
  8. Enhanced immunogenicity of a recombinant genital warts vaccine adjuvanted with monophosphoryl lipid A. Thompson, H.S., Davies, M.L., Watts, M.J., Mann, A.E., Holding, F.P., O'Neill, T., Beech, J.T., Thompson, S.J., Leesman, G.D., Ulrich, J.T. Vaccine (1998) [Pubmed]
  9. Neuropsychiatric systemic lupus erythematosus presenting as amyotrophic lateral sclerosis. Maldonado, M.E., Williams, R.C., Adair, J.C., Hart, B.L., Gregg, L., Sibbitt, W.L. J. Rheumatol. (2002) [Pubmed]
  10. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Evans, J.T., Cluff, C.W., Johnson, D.A., Lacy, M.J., Persing, D.H., Baldridge, J.R. Expert review of vaccines. (2003) [Pubmed]
  11. Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation. Heller, P.G., Glembotsky, A.C., Gandhi, M.J., Cummings, C.L., Pirola, C.J., Marta, R.F., Kornblihtt, L.I., Drachman, J.G., Molinas, F.C. Blood (2005) [Pubmed]
  12. A novel MPL point mutation resulting in thrombopoietin-independent activation. Abe, M., Suzuki, K., Inagaki, O., Sassa, S., Shikama, H. Leukemia (2002) [Pubmed]
  13. The human homolog of the myeloproliferative virus maps to chromosome band 1p34. Le Coniat, M., Souyri, M., Vigon, I., Wendling, F., Tambourin, P., Berger, R. Hum. Genet. (1989) [Pubmed]
  14. Association of single nucleotide polymorphisms in the thrombopoietin-receptor gene, but not the thrombopoietin gene, with differences in platelet count. Zeng, S.M., Murray, J.C., Widness, J.A., Strauss, R.G., Yankowitz, J. Am. J. Hematol. (2004) [Pubmed]
  15. Thrombocytosis in preterm infants: a possible involvement of thrombopoietin receptor gene expression. Nakayama, H., Ihara, K., Hikino, S., Yamamoto, J., Nagatomo, T., Takemoto, M., Hara, T. J. Mol. Med. (2005) [Pubmed]
  16. Hereditary thrombocythaemia is a genetically heterogeneous disorder: exclusion of TPO and MPL in two families with hereditary thrombocythaemia. Wiestner, A., Padosch, S.A., Ghilardi, N., Cesar, J.M., Odriozola, J., Shapiro, A., Skoda, R.C. Br. J. Haematol. (2000) [Pubmed]
  17. Expression of thrombopoietin and thrombopoietin receptor MPL in human leukemia-lymphoma and solid tumor cell lines. Graf, G., Dehmel, U., Drexler, H.G. Leuk. Res. (1996) [Pubmed]
  18. Expression of c-Mpl and c-Mpl ligand gene in hematopoietic cells of individuals with and without myeloproliferative disorders and leukemia cell lines. Sasaki, A., Katoh, O., Kawaishi, K., Hyodo, H., Kimura, A., Satow, Y., Kuramoto, A. Int. J. Hematol. (1995) [Pubmed]
  19. Cytosolic Ca(2+) levels and DNA synthesis of human umbilical vein endothelial cell cultures are unresponsive to thrombopoietin treatment. Metzen, E., Giesen, G., Fandrey, J., Jelkmann, W. Cell. Physiol. Biochem. (2001) [Pubmed]
  20. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Giannini, S.L., Hanon, E., Moris, P., Van Mechelen, M., Morel, S., Dessy, F., Fourneau, M.A., Colau, B., Suzich, J., Losonksy, G., Martin, M.T., Dubin, G., Wettendorff, M.A. Vaccine (2006) [Pubmed]
  21. A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections. Drachenberg, K.J., Wheeler, A.W., Stuebner, P., Horak, F. Allergy (2001) [Pubmed]
  22. Native and asialo-Tamm-Horsfall glycoproteins as important ligands for the detection of GalNAc beta 1-->and Gal beta 1-->4GlcNAc active lectins. Wu, A.M., Watkins, W.M., Song, S.C., Herp, A., Wu, J.H. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  23. Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes. Deveaux, S., Filipe, A., Lemarchandel, V., Ghysdael, J., Roméo, P.H., Mignotte, V. Blood (1996) [Pubmed]
  24. Cloning and characterization of the human megakaryocyte growth and development factor (MGDF) gene. Chang, M.S., McNinch, J., Basu, R., Shutter, J., Hsu, R.Y., Perkins, C., Mar, V., Suggs, S., Welcher, A., Li, L. J. Biol. Chem. (1995) [Pubmed]
  25. Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis. Chaligné, R., James, C., Tonetti, C., Besancenot, R., Le Couédic, J.P., Fava, F., Mazurier, F., Godin, I., Maloum, K., Larbret, F., Lécluse, Y., Vainchenker, W., Giraudier, S. Blood (2007) [Pubmed]
  26. Inhibition of TPO-induced MEK or mTOR activity induces opposite effects on the ploidy of human differentiating megakaryocytes. Guerriero, R., Parolini, I., Testa, U., Samoggia, P., Petrucci, E., Sargiacomo, M., Chelucci, C., Gabbianelli, M., Peschle, C. J. Cell. Sci. (2006) [Pubmed]
  27. The cytoplasmic domain of Mpl receptor transduces exclusive signals in embryonic and fetal hematopoietic cells. Challier, C., Cocault, L., Berthier, R., Binart, N., Dusanter-Fourt, I., Uzan, G., Souyri, M. Blood (2002) [Pubmed]
  28. The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells. Matsumura, I., Kanakura, Y., Kato, T., Ikeda, H., Horikawa, Y., Ishikawa, J., Kitayama, H., Nishiura, T., Tomiyama, Y., Miyazaki, H., Matsuzawa, Y. Blood (1996) [Pubmed]
  29. Basic sciences of the myeloproliferative diseases: pathogenic mechanisms of ET and PV. Gale, R.E. Int. J. Hematol. (2002) [Pubmed]
  30. Phorbol ester PMA induces expression of the thrombopoietin receptor MPL in leukemia cells. Graf, G., Zaborski, M., Quentmeier, H., Drexler, H.G. Leuk. Lymphoma (1996) [Pubmed]
  31. Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia. Corazza, F., Hermans, C., D'Hondt, S., Ferster, A., Kentos, A., Benoît, Y., Sariban, E. Blood (2006) [Pubmed]
  32. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Emmons, R.V., Reid, D.M., Cohen, R.L., Meng, G., Young, N.S., Dunbar, C.E., Shulman, N.R. Blood (1996) [Pubmed]
  33. Endogenous serum thrombopoietin concentrations in patients with myelodysplastic syndromes. Zwierzina, H., Rollinger-Holzinger, I., Nuessler, V., Herold, M., Meng, Y.G. Leukemia (1998) [Pubmed]
 
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