Detection of BCR-ABL1 kinase domain mutations causing imatinib resistance in chronic myelogenous leukemia

Franklin R. Moore, Fei Yang, Richard D. Press

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Scopus citations

Abstract

The reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11), Philadelphia chromosome] creates a BCR-ABL1 fusion protein that occurs in approximately 95% of cases of chronic myelogenous leukemia (CML), 15% of cases of adult acute lymphoblastic leukemia, and 5% of adult cases of acute myeloid leukemia. The BCR-ABL1 protein is a constitutively activated tyrosine kinase that induces and maintains the neoplastic phenotype in these leukemias. PCR-based methods to identify and quantitate the tumor-specific BCR-ABL1 RNA have been shown to be an ultrasensitive diagnostic, prognostic, and monitoring tool for Philadelphia-positive leukemias. A novel tyrosine kinase inhibitor (TKI), imatinib, has been confirmed as an effective targeted treatment in most CML patients. However, a significant minority of patients being treated with imatinib develop resistance to the drug as evidenced by rising BCR-ABL1 levels. The most common mechanism of resistance in these patients is the development of mutations in the BCR-ABL1 kinase domain (KD) that abrogate binding of imatinib. Although KD mutations are quite heterogeneous, the identification of the exact mutation site is clinically important, as some mutations, but not others, can be effectively treated with second-generation TKIs. One mutation, T315I, for example, renders the leukemia resistant to all first- and second-line TKIs. Thus, DNA sequencing of the BCR-ABL1 kinase domain in resistant patients helps identify those who may benefit from a change in TKI agents, or those who should be considered for other therapeutic measures, such as stem cell transplantation. We describe here a method for sequencing the BCR-ABL1 kinase domain in peripheral blood or bone marrow of CML patients.

Original languageEnglish (US)
Title of host publicationHematological Malignancies
Pages25-39
Number of pages15
DOIs
StatePublished - Sep 4 2013

Publication series

NameMethods in Molecular Biology
Volume999
ISSN (Print)1064-3745

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Keywords

  • BCR-ABL1
  • Chronic myelogenous leukemia
  • Dasatinib
  • Imatinib
  • Major molecular response
  • Nilotinib
  • Philadelphia chromosome
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

Moore, F. R., Yang, F., & Press, R. D. (2013). Detection of BCR-ABL1 kinase domain mutations causing imatinib resistance in chronic myelogenous leukemia. In Hematological Malignancies (pp. 25-39). (Methods in Molecular Biology; Vol. 999). https://doi.org/10.1007/978-1-62703-357-2-2