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.

  • Correspondence
  • Published:

Marked ploidy and BCR-ABL gene amplification in vivo in a patient treated with STI571

Leukemia volume 15, pages 1795–1797 (2001)Cite this article

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder arising from a neoplastic transformation in a stem cell capable of differentiating into myeloid, erythroid, megakaryocytic, B-lymphoid and occasionally T-lymphoid cell lineages. The hallmark of the disease is the Philadelphia (Ph) chromosome formed from a reciprocal translocation t(9;22)(q34;q11), found in up to 95% of the cases. The molecular consequence of this translocation is the creation of the BCR-ABL fusion gene which encodes the P210BCR-ABL hybrid protein. This protein is a constitutively active cytoplasmic tyrosine kinase. Two lines of evidence support the concept that BCR-ABL plays a central role in the pathogenesis of CML: (1) retroviral transduction experiments in which P210BCR-ABL expressed in murine bone marrow cells resulted in a myeloproliferative disorder resembling CMI;1 and (2) a novel agent, STI571 (Glivec or Imatinab Mesylate), a tyrosine kinase inhibitor with relative selectivity for inhibiting the BCR-ABL fusion protein in mice and the growth of human Ph-positive, BCR-ABL positive cells in vitro and in vivo.2 STI571 is a synthetic compound that was rationally designed to compete with ATP for the binding site of tyrosine kinases. STI571 inhibition of the Ph-positive, BCR-ABL fusion positive cells represents a major therapeutic advance in the management of CML. Since clinical trials with STI571 started in 1999, over 5000 patients have been treated with it.

Here we report a patient who was enrolled on multinational trial of STI571 in interferon-resistant patients and 3 months later developed triploidy, as well as amplification of the BCR-ABL gene. The patient was a 60-year-old woman who was diagnosed with Ph-positive CML in 1995. At that time, her white cell count (WBC) was 25 000/mm3 with hemoglobin of 12.7 g/dl, a hematocrit of 38% and platelets of 300 000/mm3. Initially she was treated with interferon alpha for 1 year. Although she remained stable during that time and her WBC counts decreased, she did not show a cytogenetic response. In 1997, Ara-C was added to her treatment regimen with no significant response. In June 2000, the patient was enrolled in an STI571 clinical trial (dose of 400 mg/day) when she showed evidence of disease progression manifested by an enlarging spleen, WBC count of 51 000/mm3, anemia and thrombocytopenia. A bone marrow biopsy and aspirate performed prior to enrollment in the study were consistent with chronic phase CML. Cytogenetics studies showed 46,XX,t(9;22)(q34;q11.2). Interphase FISH analysis with BCR-ABL ES (extra sensitive) probe (Vysis, Downers Grove, IL, USA) showed that 91% of her cells were positive for the BCR-ABL fusion gene.

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

References

  1. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome Science 1990 247: 824–830

    Article  CAS  Google Scholar 

  2. Druker BJ, Lydon NB . Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia J Clin Invest 2000 105: 3–7

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Fernandes Reese S, 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  Google Scholar 

  5. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV . Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor ST1571: diverse mechanism of resistance Blood 2000 96: 1070–1079

    CAS  PubMed  Google Scholar 

  6. Mohammed M, Shin S, Deng S, Ford J, Paquette RL, Sawyers CL . BCR/ABL gene amplification: a possible mechanism of drug resistance in patients treated with an ABL specific kinase inhibitor Blood 2000 96: Abstr. 1486

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology, The Mount Sinai School of Medicine, New York, NY

    A Sirulink & V Najfeld

  2. Department of Medicine, Tumor Cytogenetics Laboratory, The Mount Sinai School of Medicine, New York, NY

    V Najfeld

  3. Division of Hematology-Oncology, Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA

    RT Silver

Authors
  1. RT Silver
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Najfeld
    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

Sirulink, A., Silver, R. & Najfeld, V. Marked ploidy and BCR-ABL gene amplification in vivo in a patient treated with STI571. Leukemia 15, 1795–1797 (2001). https://doi.org/10.1038/sj.leu.2402267

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402267

This article is cited by

Search

Advanced search

Quick links