hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia

OCT-1 function varies with cell lineage but is not influenced by BCR-ABL

“…Two recent studies have demonstrated that polymorphonuclear cells had a higher OCT-1 mRNA expression compared with mononuclear cells in normal peripheral blood. 21,22 Studies presented here show that neutrophils express significantly higher levels of OCT-1 mRNA than lymphocytes in normal, CML diagnosis and CML remission peripheral blood and that mRNA expression relates closely to OCT-1 activity. Bazeos et al 21 subsequently examined OCT-1 mRNA expression in total white blood cells between CML diagnosis, CML remission and normal donors and found that OCT-1 mRNA expression was increased in CML remission and normal individuals compared to CML diagnosis.…”

“…myelocytes and metamyelocytes) which are not seen in normal peripheral blood. These differences in the total white blood cell population may be influencing the results of Bazeos et al 21 To overcome this, we have compared OCT-1 activity and mRNA expression in the mature neutrophil population recovered from CML diagnosis, CML remission and normal donors and have found no significant difference in OCT-1 activity or expression. Furthermore, we found no difference in OCT-1 activity and expression in the HL60 cell line transfected with control vector or BCR-ABL, indicating that BCR-ABL is unlikely to be affecting OCT-1 activity or expression.…”

“…19 Furthermore, we have established that OCT-1 activity is a strong predictor of event-free and transformation-free survival following five years of imatinib treatment. 19 It has recently been suggested that OCT-1 mRNA expression is increased in polymorphonuclear cells compared to mononuclear cells 21,22 and that BCR-ABL may have an inhibitory effect on OCT-1 expression. 21 Given the strong predictive value of OCT-1 activity, the present study was aimed at identifying factors which may influence patient variation in OCT-1 activity.…”

“…19 It has recently been suggested that OCT-1 mRNA expression is increased in polymorphonuclear cells compared to mononuclear cells 21,22 and that BCR-ABL may have an inhibitory effect on OCT-1 expression. 21 Given the strong predictive value of OCT-1 activity, the present study was aimed at identifying factors which may influence patient variation in OCT-1 activity. Specifically, the effects of cell lineage, cell maturity and BCR-ABL expression on OCT-1 activity were assessed.…”

Measurement of imatinib uptake by flow cytometry

“…For example, the expression levels of plasma membrane pumps (particularly OCT-1), which could be proportional to the membrane surface, appear to be higher in PMN than in MNC (30). Moreover, membrane pump activity may be a determining factor, which could be modulated quite extensively by certain polymorphisms (31,32), but the intrinsic characteristics of the clone responsible for IM accumulation as a result of genetic, epigenetic, and environmental factors (33) remain unknown. Overall, this observation demonstrates that it is necessary to compare cell subpopulations that are cytologically equivalent, which is possible with our method without cell immunoselection, as, for example, the CD34 1 subset.…”