Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity

• Published in: Leukemia Vol. 24; no. 4; pp. 765 - 770
• Main Authors: Engler, J R, Frede, A, Saunders, V A, Zannettino, A C W, Hughes, T P, White, D L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2010; Nature Publishing Group
• Subjects: 631/92/436/1729; 692/699/67/1990/283/1896; Adrenergic alpha-Antagonists - pharmacology; Antigens, CD34 - metabolism; Apoptosis; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Benzamides; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cancer Research; CD34 antigen; Cells (biology); Chronic myeloid leukemia; Critical Care Medicine; Drug therapy; Flow Cytometry; Gene expression; Genetic aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Imatinib; Imatinib Mesylate; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes (mononuclear); Medical sciences; Medicine; Medicine & Public Health; Myeloid leukemia; Oct-1 protein; Oncology; Organic cation transporter; Organic Cation Transporter 1 - antagonists & inhibitors; Organic Cation Transporter 1 - genetics; Organic Cation Transporter 1 - metabolism; original-article; Pharmaceuticals; Philadelphia chromosome; Piperazines - pharmacology; Prazosin - pharmacology; Progenitor cells; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Proteins; Pyrimidines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stem cells; Tumor Cells, Cultured; Australia; South Australia Australia; imatinib; CML; OCT-1; CD34; OCT-1 Activity; Antineoplastic agent; Imatinib; Hematology; Enzyme; Tyrosine kinase inhibitor; Transferases; Stem cell; Enzyme inhibitor; Hematopoietic cell; Chronic myelogenous leukemia; Malignant hemopathy; Cell subpopulation; Biological activity; Myeloproliferative syndrome; Organic cation transporter 1; Protein-tyrosine kinase; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2010.16

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.