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

Franklin R. Moore, Fei Yang, Richard Press

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Citations (Scopus)

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 publicationMethods in Molecular Biology
Pages25-39
Number of pages15
Volume999
DOIs
StatePublished - 2013

Publication series

NameMethods in Molecular Biology
Volume999
ISSN (Print)10643745

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Mutation
Protein-Tyrosine Kinases
Leukemia
Chromosomes, Human, Pair 22
Philadelphia Chromosome
Chromosomes, Human, Pair 9
Stem Cell Transplantation
DNA Sequence Analysis
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Resistance
Acute Myeloid Leukemia
Proteins
Bone Marrow
Imatinib Mesylate
RNA
Phenotype
Polymerase Chain Reaction
Therapeutics

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

Detection of BCR-ABL1 kinase domain mutations causing imatinib resistance in chronic myelogenous leukemia. / Moore, Franklin R.; Yang, Fei; Press, Richard.

Methods in Molecular Biology. Vol. 999 2013. p. 25-39 (Methods in Molecular Biology; Vol. 999).

Research output: Chapter in Book/Report/Conference proceedingChapter

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