Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Clinical Laboratory Correlates in B ALL

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

Leukemia volume 14, pages 1598–1605 (2000)Cite this article

Abstract

Thrombopoietin (TPO) is a hematopoietic growth factor which plays a central role in normal megakaryocytopoiesis and thrombopoiesis. Although the interaction between TPO and its receptor c-Mpl encoded by the c-mpl gene is now known to be implicated in the proliferation and/or differentiation of abnormal myeloid cells and normal hematopoietic stem cells, little is known about a role of the TPO/c-Mpl system in lymphoid leukemia cells. In the present study, we first examined the expression of c-mpl/c-Mpl in 23 human lymphoid leukemic cell lines (T-lineage 4, B-lineage 19) using three distinct methods. The c-mpl mrna was detectable in as many as 20 cell lines (t-lineage 3, b-lineage 17) by reverse transcriptase-polymerase chain reaction, but its translated product, c-mpl, was demonstrable by western blot only in b-lineage cell lines. flow cytometric analysis revealed the surface c-mpl expression in 13 of 17 b-lineage cell lines, but its higher expression (>40%) was restricted in nine B-precursor cell lines, eight of which had 11q23 translocation or Philadelphia chromosome (Ph1). We also demonstrated that two of eight cell lines with 11q23 translocation or Ph1 exhibited a significant proliferative response to TPO in the 3H-thymidine uptake and colony-forming assays. Triggering of these cell lines by TPO transiently up-regulated tyrosine phosphorylation of JAK-2 and Shc, indicating that their receptor is functional. Primary leukemia cells separated from patients with B-precursor acute lymphoblastic leukemia with Ph1 or 11q23 translocation also showed the surface c-Mpl expression and a significant responsiveness to TPO. These results suggest that the TPO/c-Mpl interaction may play a physiological role in the growth regulation of B-precursor leukemia cells particularly with specific chromosomal abnormalities. Leukemia (2000) 14, 1598–1605.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kato T, Iwamatsu A, Shimada Y, Horie K, Kokubo A, Maeda E, Ogami K, Sohma Y, Akahori H, Kudo Y, Kubomura N, Matsumoto A, Tahara T, Ohashi H, Tsumura H, Inoue H, Kawamura K, Miyazaki H . Purification and characterization of thrombopoietin derived from thrombocytopenic rat plasma Blood 1994 84: 329a

    Google Scholar 

  2. Miyazaki H, Kato T, Ogami K, Iwamatsu A, Shimada Y, Souma Y, Akahori H, Horie K, Kokubo A, Kudo Y, Maeda E, Kawamura K, Sudo T . Isolation and cloning of a novel human thrombopoietic factor Exp Hematol 1994 22: 838a

    Google Scholar 

  3. Kato T, Ogami K, Shimada Y, Iwamatsu A, Sohma Y, Akahori H, Horie K, Kokubo A, Kudo Y, Maeda E, Kobayashi K, Ohashi H, Ozawa T, Inoue H, Kawamura K, Miyazaki H . Purification and characterization of human thrombopoietin J Biochem 1995 118: 229–236

    Article  CAS  PubMed  Google Scholar 

  4. de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang W-J, Oles KJ, Hultgren B, Solberg LA Jr, Goeddel DV, Eaton DL . Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand Nature 1994 369: 533–538

    Article  CAS  PubMed  Google Scholar 

  5. Lok S, Kaushansky K, Holly RD, Kuijper JL, Lofton-Day CE, Oort PJ, Grant FJ, Heipel MD, Burkhead SK, Kramer JM, Bell LA, Sprecher CA, Blumberg H, Johnson R, Prunkard D, Ching AFT, Mathewes SL, Bailey MC, Forstorm JW, Buddle MM, Osborn SG, Evans SJ, Sheppard PO, Presnell SR, O’Hara PJ, Hagen FS, Roth GJ, Foster DC . Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo Nature 1994 369: 565–568

    Article  CAS  PubMed  Google Scholar 

  6. Bartley TD, Bogenberger J, Hunt P, Li Y-S, Lu HS, Martin F, Chang MS, Samal B, Nichol JL, Swift S, Johnson MJ, Hsu Hsu E, Hokom MM, Hornkohl A, Choi E, Pangelian M, Sun Y, Mar V, McNinch J, Simonet L, Jacobsen F, Xie C, Shutter J, Chute Elliot G, Izumi R, Covey T, Crouse J, Garcia A, Xu W, Del Castillo J, Biron J, Coles S, Hu MCT, Pacifici R, Ponting I, Saris C, Wen D, Yung YP, Lin H, Bosselman RA . Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl Cell 1994 77: 1117–1124

    Article  CAS  PubMed  Google Scholar 

  7. Vigon I, Mornon JP, Cocault L, Mitjavila MT, Tambourin P, Gisselbrecht S, Souyri M . Molecular cloning and characterization of MPL, the human homologue of v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily Proc Natl Acad Sci USA 1992 89: 5640–5644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eaton DL, de Sauvage FJ . Thrombopoietin: the primary regulator of megakaryocytopoiesis and thrombopoiesis Exp Hematol 1997 25: 1–7

    CAS  PubMed  Google Scholar 

  9. Kaushansky K . Thrombopoietin: the primary regulator of platelet production Blood 1995 86: 419–431

    CAS  PubMed  Google Scholar 

  10. Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT . Functional isolation and characterization of human hematopoietic stem cells Science 1995 267: 104–108

    Article  CAS  PubMed  Google Scholar 

  11. Kaushansky K, Lin N, Grossman A, Humes J, Sprugel K, Broudy V . Thrombopoietin expands erythroid, granulocyte–macrophage, and megakaryocyte progenitor cells in normal and myelosuppressed mice Exp Hematol 1996 24: 265–269

    CAS  PubMed  Google Scholar 

  12. Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D . Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking in the thrombopoietin receptor c-Mpl Blood 1996 87: 2162–2170

    CAS  PubMed  Google Scholar 

  13. Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue C, de Sauvage FJ, Eaton DL . Role of c-mpl in early hematopoiesis Blood 1998 92: 4–10

    CAS  PubMed  Google Scholar 

  14. Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M . Recombinant human thrombopoietin (Mpl ligand) enhances proliferation of erythroid progenitors Blood 1995 86: 2494–2499

    CAS  PubMed  Google Scholar 

  15. Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M . Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with steel factor and/or interleukin-3 Blood 1996 88: 429–436

    CAS  PubMed  Google Scholar 

  16. Borge OJ, Ramsfjell V, Veiby OP, Murphy Jr MJ, Lok S, Jacobsen SEW . Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro Blood 1996 88: 2859–2870

    CAS  PubMed  Google Scholar 

  17. Young JC, Bruno E, Luens KM, Wu S, Backer M, Murray LJ . Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+ Thy-1+ Lin− primitive progenitor cells Blood 1996 88: 1619–1631

    CAS  PubMed  Google Scholar 

  18. Katayama N, Itoh R, Kato T, Sugawara T, Mahmud N, Ohishi K, Masuya M . Role for c-mpl and its ligand thrombopoietin in early hematopoiesis Leuk Lymphoma 1997 28: 51–56

    Article  CAS  PubMed  Google Scholar 

  19. Ku H, Yoneyama Y, Kaushansky K, Ogawa M . Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice Blood 1996 87: 4544–4551

    CAS  PubMed  Google Scholar 

  20. Vigon I, Dreyfus F, Melle J, Viguie F, Ribrag V, Cocault L, Souyri M, Gisselbrecht S . Expression of the c-mpl proto-oncogene in human hematologic malignancies Blood 1993 82: 877–883

    CAS  PubMed  Google Scholar 

  21. Matsumura I, Kanakura Y, Kato T, Ikeda H, Ishikawa J, Horikawa Y, Hashimoto K, Moriyama Y, Tsujimura T, Nishiura T, Miyazaki H, Matsuzawa Y . Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin Blood 1995 86: 703–709

    CAS  PubMed  Google Scholar 

  22. Matsumura I, Kanakura Y, Ikeda H, Ishikawa J, Yoshida H, Horikawa Y, Nishiura T, Tahara T, Kato T, Miyazaki H, Matsuzawa Y . Coexpression of thrombopoietin and c-mpl genes in human acute myeloblastic leukemia cells Leukemia 1996 10: 91–94

    CAS  PubMed  Google Scholar 

  23. Matsumura I, Kanakura Y, Kato T, Ikeda H, Horikawa Y, Ishiwaka J, Kitayama H, Nishiura T, Tomiyama Y, Miyazaki H, Matsuzawa Y . The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells Blood 1996 88: 3074–3082

    CAS  PubMed  Google Scholar 

  24. Drexler HG, Quentmeier H . Use of human leukemia–lymphoma cell lines in hematological research: effects of thrombopoietin on human leukemia cell lines Hum Cell 1996 9: 309–316

    CAS  PubMed  Google Scholar 

  25. Graf G, Dehmel U, Drexler HG . Expression of thrombopoietin and thrombopoietin receptor MPL in human leukemia–lymphoma and solid tumor cell lines Leuk Res 1996 20: 831–838

    Article  CAS  PubMed  Google Scholar 

  26. Nakamura M, Sugita K, Inukai T, Goi K, Iijima K, Tezuka T, Kojika S, Shiraishi K, Miyamoto N, Karakida N, Kagami K, O-Koyama T, Mori T, Nakazawa S . p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood acute lymphoblastic leukemia with 11q23 translocation Leukemia 1999 13: 884–890

    Article  CAS  PubMed  Google Scholar 

  27. Sugita K, Mori T, Yokota S, Kuroki M, O-Koyama T, Inukai T, Iijima K, Goi K, Tezuka T, Kojika S, Shiraishi K, Nakamura M, Miyamoto N, Kagami K, Nakazawa S . The KOR-SA3544 antigen predominantly expressed on the surface of Philadelphia chromosome-positive acute lymphoblastic leukemia cells is nonspecific cross-reacting antigen-50/90 (CD66c) and invariably expressed in cytoplasm of human leukemia cells Leukemia 1999 13: 779–785

    Article  CAS  PubMed  Google Scholar 

  28. Inukai T, Sugita K, Iijima K, Goi K, Tezuka T, Kojika S, Kagami K, Mori T, Kinoshita A, Suzuki T, O-Koyama T, Nakazawa S . Leukemic cells with 11q23 translocations express granulocyte colony-stimulating factor (G-CSF) receptor and their proliferation is stimulated with G-CSF Leukemia 1998 12: 382–389

    Article  CAS  PubMed  Google Scholar 

  29. Drachman JG, Sabath DF, Fox NE, Kaushansky K . Thrombopoietin signal transduction in purified murine megakaryocytes Blood 1997 89: 483–492

    CAS  PubMed  Google Scholar 

  30. Drachman JG, Griffin JD, Kaushansky K . The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl J Biol Chem 1995 270: 4979–4982

    Article  CAS  PubMed  Google Scholar 

  31. Miyakawa Y, Oda A, Druker BJ, Kato T, Miyazaki H, Handa M, Ikeda Y . Recombinant thrombopoietin induced rapid protein tyrosine phosphorylation of Janus Kinase 2 and Shc in human blood platelets Blood 1995 86: 23–27

    CAS  PubMed  Google Scholar 

  32. Sattler M, Durstin MA, Frank DA, Okuda K, Kaushansky, Salgia R, Griffin JD . The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases Exp Hematol 1995 23: 1040–1048

    CAS  PubMed  Google Scholar 

  33. Drexler HG, Quentmier H . Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells Leukemia 1996 10: 1405–1421

    CAS  PubMed  Google Scholar 

  34. Takeshita A, Shinjo K, Izumi M, Ling P, Nakamura S, Naito K, Ohnishi K, Ohno R . Quantitative expression of thrombopoietin receptor on leukemia cells from patients with acute myeloid leukaemia and acute lymphoblastic leukaemia Br J Haematol 1998 100: 283–290

    Article  CAS  PubMed  Google Scholar 

  35. Inukai T, Sugita K, Mitsui K, Iijima K, Goi K, Tezuka T, Kojika S, Kagami K, Mori T, Kinoshita A, Suzuki T, Okazaki-Koyama T, Nakazawa S . Participation of granulocyte colony-stimulating factor in the growth regulation of leukemia cells from Philadelphia chromosome-positive acute leukemia and blast crisis of chronic myeloid leukemia Leukemia 2000 14: 1386–1395

    Article  CAS  PubMed  Google Scholar 

  36. Hokom MM, Lacey D, Kinstler OB, Choi E, Kaufman S, Faust J, Rowan C, Dwyer E, Nichol JL, Grasel T, Wilson J, Steinbrink R, Hecht R, Winter D, Boone T, Hunt P . Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice Blood 1995 86: 4486–4492

    CAS  PubMed  Google Scholar 

  37. Akahori H, Shibuya K, Obuchi M, Nishizawa Y, Tsuji A, Kabaya K, Kusaka M, Ohashi H, Tsumura H, Kato T, Miyazaki H . Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy-induced thrombocytopenia Br J Haematol 1996 94: 722–728

    Article  CAS  PubMed  Google Scholar 

  38. Geissler K, Kabrna E, Stengg S, Schwarzinger I, Knöbl P, Valent P, Eichinger S, Barge A, Lechner K . Recombinant human megakaryocyte growth and development factor increases levels of circulating haemopoietic progenitor cells post chemotherapy in patients with acute myeloid leukemia Br J Haematol 1998 102: 535–543

    Article  CAS  PubMed  Google Scholar 

  39. Miyazaki H . Update on thrombopoietin in preclinical and clinical trials Curr Opin Hematol 1998 5: 197–202

    Article  CAS  PubMed  Google Scholar 

  40. Ohno R, Tomonaga M, Kobayashi T, Kanamura A, Shirakawa S, Masaoka T, Omine M, Oh H, Nomura T, Sakai Y, Hirano M, Yokomaku S, Nakayama S, Yoshida Y, Miura A, Morishita Y, Dohy H, Niho Y, Hamajima N, Takaku F . Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia New Engl J Med 1990 323: 871–877

    Article  CAS  PubMed  Google Scholar 

  41. Bettelheim P, Valent P, Andreef M, Tafuri A, Haimi J, Gorischek C, Muhm M, Sillaber C, Haas O, Veider L, Maurer D, Schulz G, Speiser W, Geissler K, Kier P, Hinterberger W, Lechner K . Recombinant human granulocyte–macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia Blood 1991 77: 700–711

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Yamanashi Medical University, Yamanashi, Japan

    K Iijima, K Sugita, T Inukai, K Goi, T Tezuka, K Uno, H Sato, K Kagami & S Nakazawa

Authors
  1. K Iijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Sugita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Inukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Goi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Tezuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Uno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Kagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iijima, K., Sugita, K., Inukai, T. et al. Expression of thrombopoietin receptor and its functional role in human B-precursor leukemia cells with 11q23 translocation or Philadelphia chromosome. Leukemia 14, 1598–1605 (2000). https://doi.org/10.1038/sj.leu.2401893

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401893

Keywords

This article is cited by

Search

Advanced search

Quick links