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OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1

Leukemia volume 24, pages 1962–1965 (2010)Cite this article

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The majority of chronic phase-chronic myeloid leukaemia (CP-CML) patients respond well to the first generation tyrosine kinase inhibitor, imatinib. However, 25–30% of patients fare less well, exhibiting suboptimal response or treatment failure. We have demonstrated that the functional activity of the OCT-1 protein (termed OCT-1 activity) assayed in patient mononuclear cells before the start of imatinib therapy is a key determinant of both short- and long-term response to imatinib in previously untreated CP-CML.1, 2 A greater proportion of patients with high OCT-1 activity (> median value defined in the Tidel study of 7.2 ng per 200 000 cells)1 achieve major molecular response (MMR) when compared with patients with low OCT-1 activity (89 vs 55%; P=0.007). Furthermore, a low OCT-1 activity is significantly associated with lower overall survival to 5 years (87 vs 96%; P=0.028) and event-free survival (48 vs 74%; P=0.03), as well as a higher Abl kinase domain mutation rate (21 vs 4%; P=0.047). The interpatient variability observed in OCT-1 activity remains unexplained. It has been suggested that the level of OCT-1 mRNA is predictive of response to imatinib,3 however this has yet to be demonstrated in a large cohort of previously untreated patients. It is possible that non-synonymous, single-nucleotide polymorphisms (SNPs) that result in an altered OCT-1 protein may well impact on the functional activity of this protein and, therefore, on response to therapy.

In a recent publication Bazeos et al.4 explored SNPs as possible predictive factors for imatinib response. In this study they investigated the frequency of seven previously reported SNPs in a cohort of 132 CML patients treated with imatinib in chronic phase. They also explored, the impact of four of these SNP's (R61C, P341L, G401S and rs6222342) on the achievement of MMR, and found that the G401S (rs34130495) SNP was significantly associated with a higher rate of MMR (P=0.0155). It is interesting that this polymorphism has been previously described by Shu and Kerb5, 6 and has been demonstrated to result in a reduced function protein with respect to transport of the model OCT-1 substrates MPP and tetraethylammonium (TEA). Thus, its association with an increased rate of MMR is surprising. It is also evident that the frequency of this SNP is low (frequency in the tested population 0.045, frequency in European Americans Shu 0.011),5 thus its presence would not account for many cases of MMR observed in CP-CML patients treated with imatinib.

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References

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Acknowledgements

Many thanks to Dr Susan Branford for her assistance with primer design.

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Authors and Affiliations

  1. Haematology Department, SA Pathology (RAH Campus), Adelaide, South Australia, Australia

    D L White, V A Saunders, P Dang, J Engler & T P Hughes

  2. Centre for Cancer Biology, Adelaide, South Australia, Australia

    D L White, V A Saunders, P Dang, J Engler & T P Hughes

  3. Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    D L White, J Engler & T P Hughes

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  1. D L White
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Correspondence to D L White.

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White, D., Saunders, V., Dang, P. et al. OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia 24, 1962–1965 (2010). https://doi.org/10.1038/leu.2010.188

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