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An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia

Leukemia volume 22, pages 2269–2272 (2008)Cite this article

Mutations in the kinase domain of BCR-ABL that impair drug binding are the best characterized mechanism of imatinib resistance in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia.1 Some patients without kinase domain mutation-based resistance exhibit increased BCR-ABL expression.2 However, in a sizable proportion of patients, neither of these mechanisms is demonstrable.3 Causes of imatinib resistance implicated in such patients include insufficient intracellular drug levels due to increased efflux or reduced influx or sequestration of imatinib through increased plasma protein binding.2 Further, some kinase domain mutation-negative patients appear to have truly BCR-ABL-independent imatinib resistance, for example, through the activation of SRC family kinases or adaptive granulocyte-macrophage colony-stimulating factor secretion.4, 5 A myeloproliferative disease with features of CML can be induced by a variety of genetic lesions, including activating mutations of RAS, PTPN11, JAK2 and receptor tyrosine kinases such as FLT3. We therefore hypothesized that patients with acquired imatinib resistance but no evidence of BCR-ABL mutations or gene amplification may have activating mutations in such imatinib-insensitive pathways or that they may have acquired resistance mutations in the imatinib targets KIT and platelet-derived growth factor receptor α/β.

We identified a total of 17 imatinib-resistant CML patients (nine males and eight females) with a median age of 57 years (range: 34–69 years) (Table 1) who had no evidence of a BCR-ABL mutation on standard diagnostic sequencing. At the time of the study, cytogenetic analysis revealed a median of 40% (range: 10–100%) Ph-positive metaphases, fluorescence in situ hybridization showed a median of 43% (range: 1.5–98.5%) BCR-ABL-positive interphases, and quantitative PCR showed a BCR-ABL/G6PD median ratio of 2.5% (range: 0.52–210%). Out of the 17 patients, 10 never achieved a complete cytogenetic response before this study and seven had lost this level of response at the time of sampling. Sequence analysis of BCR-ABL covering the Cap, SH3, SH2 and kinase domains of ABL (exons 1–9) confirmed the absence of mutations. Mutation screening of KRAS (exons 3–5), NRAS (exons 2–5), PTPN11 (exons 3, 4, 8 and 13), KIT (entire coding region), FLT3 (exons 14 and 20), JAK2 (exon 14), PDGFRα (exons 12, 14 and 18) and PDGFRβ (exons 11 and 17) revealed several previously described polymorphisms, but no novel mutations were detected. One of 17 patients (5.8%) harbored a missense mutation (C → T) in exon 3 of KRAS leading to replacement of threonine 58 with isoleucine (T58I). Approximately 30% of amplicons were mutant, as confirmed by bidirectional sequencing of three independently amplified PCR products.

Table 1 Characteristics of the patient cohort
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Acknowledgements

This study was supported in part by NHLBI Grant HL082978-01 (MWD) and by the Leukemia and Lymphoma Society (MWD).

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Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, USA

    A Agarwal, C A Eide, A Harlow, A S Corbin, M J Mauro, B J Druker, C L Corless, M C Heinrich & M W Deininger

  2. Division of Hematology and Medical Oncology, Howard Hughes Medical Institute, Portland, OR, USA

    A Agarwal, C A Eide, A S Corbin & B J Druker

  3. Portland Veterans Affairs Medical Center, Portland, OR, USA

    A Harlow, C L Corless & M C Heinrich

  4. Department of Pathology, Oregon Health & Science University, Portland, OR, USA

    A Harlow & C L Corless

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Correspondence to M W Deininger.

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Agarwal, A., Eide, C., Harlow, A. et al. An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia 22, 2269–2272 (2008). https://doi.org/10.1038/leu.2008.124

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