Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity.

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.

• Authors: J R Engler, A Frede, V A Saunders, A C W Zannettino, T P Hughes, D L White
• Journal: Leukemia (Leukemia) Vol. 24 Issue 4 Pg. 765-70 (Apr 2010) ISSN: 1476-5551 [Electronic] England
• PMID: 20147974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Adrenergic alpha-Antagonists
• Antigens, CD34
• Benzamides
• Organic Cation Transporter 1
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• RNA, Messenger
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Prazosin

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Adrenergic alpha-Antagonists (pharmacology)
• Antigens, CD34 (metabolism)
• Benzamides
• Bone Marrow Cells (drug effects, metabolism, pathology)
• Flow Cytometry
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Organic Cation Transporter 1 (antagonists & inhibitors, genetics, metabolism)
• Piperazines (pharmacology)
• Prazosin (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured