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.

  • Spotlight
  • Published:

Spotlight on IMATINIB as a Model for Signal Transduction Inhibitors

Effects of imatinib on bone marrow engraftment in syngeneic mice

Leukemia volume 16, pages 1584–1588 (2002)Cite this article

Abstract

Chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias arise from the genetic reciprocal translocation t(9;22), forming the BCR-ABL fusion gene. These lead to the expression of the constitutively active tyrosine kinase BCR-ABL, which is the causative oncogene for these leukemias. Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) is currently considered the only curative treatment for chronic myeloid leukemia (CML). Recently, the selective tyrosine kinase inhibitor imatinib mesylate (Glivec, formerly STI-571) has been shown to induce durable hematologic and major cytogenetic responses in a high percentage of patients with chronic phase CML. In patients with advanced disease remissions are transient and most patients relapse despite continued imatinib treatment. Some of these patients go on to receive allogeneic BMT or SCT, during which administration of imatinib is usually discontinued as it is believed to interfere with bone marrow engraftment. In this study, we examined the effect of imatinib on hematopoietic engraftment in a syngeneic mouse model. We found that imatinib has no significant influence on hematopoietic recovery in lethally irradiated mice in vivo. Thus, our results suggest that continued administration of imatinib in the course of BMT or SCT may be a feasible therapeutic regimen.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM . The biology of chronic myeloid leukemia N Engl J Med 1999 341: 164–172

    Article  CAS  PubMed  Google Scholar 

  2. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

    Article  CAS  PubMed  Google Scholar 

  3. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B . Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia N Engl J Med 2002 346: 645–652

    Article  CAS  PubMed  Google Scholar 

  4. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M . Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N Engl J Med 2001 344: 1038–1042

    Article  CAS  PubMed  Google Scholar 

  5. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL . Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study Blood 2002 99: 1928–1937

    Article  CAS  PubMed  Google Scholar 

  6. Goldman J . Implications of imatinib mesylate for hematopoietic stem cell transplantation Semin Hematol 2001 38: 28–34

    Article  CAS  PubMed  Google Scholar 

  7. Carella AM, Lerma E, Corsetti MT, Dejana A, Basta P, Vassallo F, Abate M, Soracco M, Benvenuto F, Figari O, Podesta M, Piaggio G, Ferrara R, Sessarego M, Parodi C, Pizzuti M, Rubagotti A, Occhini D, Frassoni F . Autografting with Philadelphia chromosome-negative mobilized hematopoietic progenitor cells in chronic myelogenous leukemia Blood 1999 93: 1534–1539

    CAS  PubMed  Google Scholar 

  8. von Bubnoff N, Schneller F, Peschel C, Duyster J . BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study Lancet 2002 359: 487–491

    Article  CAS  PubMed  Google Scholar 

  9. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification Science 2001 293: 876–880

    Article  CAS  PubMed  Google Scholar 

  10. Hochhaus A, Kreil S, Corbin A, La Rosee P, Lahaye T, Berger U, Cross NC, Linkesch W, Druker BJ, Hehlmann R, Gambacorti-Passerini C, Corneo G, D'Incalci M . Roots of clinical resistance to STI-571 cancer therapy Science 2001 293: 2163a

    Article  Google Scholar 

  11. Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP . High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance Blood 2002 99: 3472–3475

    Article  CAS  PubMed  Google Scholar 

  12. Hofmann WK, Jones LC, Lemp NA, de Vos S, Gschaidmeier H, Hoelzer D, Ottmann OG, Koeffler HP . Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation Blood 2002 99: 1860–1862

    Article  PubMed  Google Scholar 

  13. Fischer T . Results up to now of administration of STI-571 (Glivec) in recurrence after allogenic and autologous stem cell transplantation in chronic myeloid leukemia Med Klin 2002 97 (Suppl. 1): 22–27

    Google Scholar 

  14. Wassmann B, Klein SA, Scheuring U, Pfeifer H, Martin H, Gschaidmeier H, Hoelzer D, Ottmann OG . Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation Bone Marrow Transplant 2001 28: 721–724

    Article  CAS  PubMed  Google Scholar 

  15. Olavarria E, Craddock C, Dazzi F, Marin D, Marktel S, Apperley JF, Goldman JM . Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation Blood 2002 99: 3861–3862

    Article  CAS  PubMed  Google Scholar 

  16. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB . Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative Cancer Res 1996 56: 100–104

    CAS  PubMed  Google Scholar 

  17. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells Nat Med 1996 2: 561–566

    Article  CAS  PubMed  Google Scholar 

  18. Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, March CJ, Boswell HS, Gimpel SD, Cosman D, Williams DE . Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms Cell 1990 63: 235–243

    Article  CAS  PubMed  Google Scholar 

  19. Nocka K, Majumder S, Chabot B, Ray P, Cervone M, Bernstein A, Besmer P . Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice – evidence for an impaired c-kit kinase in mutant mice Genes Dev 1989 3: 816–826

    Article  CAS  PubMed  Google Scholar 

  20. Nocka K, Tan JC, Chiu E, Chu TY, Ray P, Traktman P, Besmer P . Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W EMBO J 1990 9: 1805–1813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Deininger MWN, Schleuning M, Olavarria E, Fischer T, Nagler A, Sayer H, Boque C, Volin L, Piotelli G, Russel N, Wandt H, Schanz U, Greinix H, Sponk L, Verdonck L, Lennard A, Wimmer M, Hegenbart U, Lange T, Niederwieser D . Safety and efficacy of glivec prior to allografting for CML and Ph-positive ALL: European experience Bone Marrow Transplant 2002 29 (Suppl. 2): Abstr. 183

  22. Wassmann B, Pfeifer H, Scheuring U, Atta J, Martin H, Brck P, Gschaidmeier H, Hoelzer D, Ottmann OG . Salvage therapy with STI571 (glivec) prior to allogeneic stem cell transplantation (Allo Sct) in relapsed or refractory Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+All) Bone Marrow Transplant 2002 29 (Suppl. 2): Abstr. P405

  23. Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R . Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation Blood 2002 99: 3792–3800

    Article  CAS  PubMed  Google Scholar 

  24. Spangrude GJ, Heimfeld S, Weissman IL . Purification and characterization of mouse hematopoietic stem cells Science 1988 241: 58–62

    Article  CAS  PubMed  Google Scholar 

  25. Li CL, Johnson GR . Murine hematopoietic stem and progenitor cells: I. Enrichment and biologic characterization Blood 1995 85: 1472–1479

    CAS  PubMed  Google Scholar 

  26. Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, Rossi F, Gianazza E, Brueggen J, Cozens R, Pioltelli P, Pogliani E, Corneo G, Formelli F, D'Incalci M . Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR- ABL(+) leukemic cells to the abl inhibitor STI571 J Natl Cancer Inst 2000 92: 1641–1650

    Article  CAS  PubMed  Google Scholar 

  27. Wolff NC, Ilaria RL Jr . Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571 Blood 2001 98: 2808–2816

    Article  CAS  PubMed  Google Scholar 

  28. Weissman IL . Translating stem and progenitor cell biology to the clinic: barriers and opportunities Science 2000 287: 1442–1446

    Article  CAS  PubMed  Google Scholar 

  29. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL . Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro Blood 2002 99: 319–325

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant to JD and CP from the BMBF, German national genome project No 01-GS-0105 and 01-GS-015, by SFB grant No 456 to JD, KG and CP and by a grant from the Mildred-Scheel Stiftung to JD. CM is supported by a fellowship from the Deutsche Jose Carreras Leukämie Stiftung (DJCLS 2001/NAT-2). We thank H Gschaidmeier (Novartis Pharma, Nürnberg, Germany) and E Buchdunger (Novartis Pharma, Basel, Switzerland) for the generous gift of imatinib.

Author information

Author notes

  1. J Hoepfl and C Miething: J Hoepfl and C Miething contributed equally to this article

Authors and Affiliations

  1. Department of Internal Medicine III, Laboratory of Leukemogenesis, Technical University of Munich, Munich, Germany

    J Hoepfl, C Miething, R Grundler, KS Götze, C Peschel & J Duyster

Authors
  1. J Hoepfl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Miething
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Grundler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. KS Götze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Peschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Duyster
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Duyster.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoepfl, J., Miething, C., Grundler, R. et al. Effects of imatinib on bone marrow engraftment in syngeneic mice. Leukemia 16, 1584–1588 (2002). https://doi.org/10.1038/sj.leu.2402679

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402679

Keywords

This article is cited by

Search

Advanced search

Quick links