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https://hdl.handle.net/2440/60850
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Type: | Journal article |
Title: | Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity |
Author: | Engler, J. Frede, A. Saunders, V. Zannettino, A. Hughes, T. White, D. |
Citation: | Leukemia, 2010; 24(4):765-770 |
Publisher: | Nature Publishing Group |
Issue Date: | 2010 |
ISSN: | 0887-6924 1476-5551 |
Statement of Responsibility: | J.R. Engler, A. Frede, V.A. Saunders, A.C.W. Zannettino, T.P. Hughes, and D.L. White |
Abstract: | Active influx of imatinib in chronic myeloid leukemia (CML) cells is mediated by the organic cation transporter 1 (OCT-1). Functional activity of OCT-1 (OCT-1 Activity) in mononuclear cells is an excellent predictor of molecular response over the first 24 months of imatinib therapy for chronic phase patients. CML progenitor cells are less sensitive to imatinib-induced apoptosis and are likely contributors to disease persistence. We investigated whether alterations in the expression and function of OCT-1 have a role in imatinib resistance in progenitors. We found the intracellular uptake and retention (IUR) of imatinib, OCT-1 Activity and OCT-1 mRNA expression are all significantly lower in CML CD34+ cells compared with mature CD34− cells (P<0.001). However, no differences in IUR or OCT-1 Activity were observed between these subsets in healthy donors. In contrast to OCT-1, ABCB1 and ABCG2 seemed to have no functional role in the transport of imatinib in CML CD34+ cells. Consistent with the observation that nilotinib uptake is not OCT-1 dependent, the IUR of nilotinib did not differ between CML CD34+ and CD34− cells. These results indicate that low imatinib accumulation in primitive CML cells, mediated through reduced OCT-1 Activity may be a critical determinant of long-term disease persistence. |
Keywords: | CML OCT-1 OCT-1 Activity CD34+ imatinib |
Rights: | © 2010 Macmillan Publishers Limited. All rights reserved |
DOI: | 10.1038/leu.2010.16 |
Published version: | http://dx.doi.org/10.1038/leu.2010.16 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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