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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
Statement of
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
RMID: 0020094988
DOI: 10.1038/leu.2010.16
Appears in Collections:Medicine publications

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