Article thumbnail
Location of Repository

Two different point mutations in ABL gene ATP-binding domain conferring Primary Imatinib resistance in a Chronic Myeloid Leukemia (CML) patient: A case report

By Zafar Iqbal, Rubina T. Siddiqui and Javed A. Qureshi


Imatinib (Gleevec) is the effective therapy for BCR-ABL positive CML patients. Point mutations have been detected in ATP-binding domain of ABL gene which disturbs the binding of Gleevec to this target leading to resistance. Detection of mutations is helpful in clinical management of imatinib resistance. We established a very sensitive (ASO) PCR to detect mutations in an imatinib-resistant CML patient. Mutations C944T and T1052C were detected which cause complete partial imatinib resistance, respectively. This is the first report of multiple point mutations conferring primary imatinib resistance in same patient at the same time. Understanding the biological reasons of primary imatinib resistance is one of the emerging issues of pharmacogenomics and will be helpful in understanding primary resistance of molecularly-targeted cancer therapies. It will also be of great utilization in clinical management of imatinib resistance. Moreover, this ASO-PCR assay is very effective in detecting mutations related to imatinib resistance

Topics: Research Article
Publisher: Biological Procedures Online
Year: 2004
DOI identifier: 10.1251/bpo83
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2003). A randomized study comparing interferon (IFN alpha) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic phase chronic myeloid leukemia (CML). Leuk Res
  2. (2003). Advances in targeted therapy for chronic myeloid leukemia. Expert Rev Anticancer Ther
  3. (2003). Analysis of the impact of imatinib mesylate therapy on the prognosis of patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha regimens for early chronic phase. Cancer
  4. (2003). Bcr-Abl mutations, resistance to imatinib, and imatinib plasma levels. Blood
  5. (2003). Chronic myeloid leukemia patients resistant to or intolerant of interferon alpha and subsequently treated with imatinib show reduced immunoglobulin levels and hypogammaglobulinemia. Haematologica
  6. (2003). Chronic myeloid leukemia-advances in biology and new approaches to treatment.
  7. (2003). Chronic myeloid leukemia: pathophysiology, diagnostic parameters, and current treatment concepts. Wien Klin Wochenschr
  8. (2001). Clinical resistance to STI -571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science
  9. (2002). Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation
  10. (2003). Comparison of two PCR-based methods and automated DNA sequencing for prop-1 genotyping in Ames dwarf mice. Mutat Res
  11. Cytogenetic and molecular mechanisms of resistance to imatinib. Semin Hematol 2003; 40(2 Suppl 3):69-
  12. (2003). Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P -loop) are associated with a poor prognosis. Blood
  13. (2003). Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood
  14. (2004). Druker BJ. In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant BcrAbl positive cell lines. Blood
  15. (2003). Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer
  16. (2003). Enhanced allele-specific PCR discrimination in SNP genotyping using 3' locked nucleic acid (LNA) primers. Hum Mutat
  17. (2003). Imatinib alone and in combination for chronic myeloid leukemia. Semin Hematol
  18. (2002). In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol
  19. (2003). Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell
  20. (1989). Molecular Cloning: A Laboratory Manual, 2nd ed.
  21. (2003). Molecular response to imatinib mesylate following relapse after allogenic SCT for CML.
  22. (2002). Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell
  23. (2003). Mutated tyrosine kinases as therapeutic targets in myeloid leukemias. Adv Exp Med Biol
  24. Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment.
  25. (2003). Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis. Semin Oncol
  26. (2003). Optimized sensitivity of allele-specific PCR for prenatal typing of human platelet alloantigen single nucleotide polymorphisms. Biotechniques
  27. (2003). Real-time PCR quantification of bcr/abl chimera and WT1 genes in chronic myeloid leukemia. Rinsho Byori
  28. (2003). Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia
  29. (2003). Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer
  30. (2003). Sensitive and quantitative detection of mutations associated with clinical resistance to STI-571. Leuk Res
  31. (2003). Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood
  32. (2002). Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood
  33. (2004). Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev Iqbal et al.
  34. (2003). STI571 as a targeted therapy for CML. Cancer Invest
  35. (2003). Sudden onset of the blastic phase of chronic myelogenous leukemia: patterns and implications. Cancer
  36. (2003). The chronic myeloproliferative disorders: an historical perspective. Curr Hematol Rep
  37. (2002). The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review. Health Technol Assess
  38. (1973). Trends in leukemia incidence and survival in the United States

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.