OCT-1 function varies with cell lineage but is not influenced by BCR-ABL.
BACKGROUND
Despite the excellent responses to imatinib therapy observed in patients with chronic phase chronic myeloid leukemia, approximately 25% of patients display primary resistance or suboptimal response. The OCT-1 activity in mononuclear cells reflects the efficiency of active influx of imatinib. OCT-1 activity in mononuclear cells is highly variable between patients and significantly correlates with a patient's molecular response to imatinib treatment and overall survival. The present study examined whether cell lineage and BCR-ABL expression influenced OCT-1 activity.


METHODS
The OCT-1 activity and OCT-1 mRNA expression was assessed in pure populations of neutrophils, monocytes and lymphocytes recovered from chronic myeloid leukemia patients at diagnosis, in cytogenetic remission and normal individuals. The role of BCR-ABL on OCT-1 activity and differentiation was examined in a cell line model of ectopic BCR-ABL expression.


RESULTS
The OCT-1 activity and OCT-1 mRNA expression was highest in the neutrophil population and lowest in lymphocytes (P<0.05). This was observed for patients at diagnosis, in cytogenetic remission and normal individuals. Interestingly, neutrophil OCT-1 activity was not significantly different between patients at diagnosis, in remission and normal donors. This was also observed for monocytes and lymphocytes. Furthermore, OCT-1 activity in mononuclear cells was significantly correlated with the OCT-1 activity in neutrophils (P=0.001). In a cell line model in which BCR-ABL was ectopically expressed, we found no evidence that BCR-ABL directly affected OCT-1 expression and function. However, BCR-ABL stimulated granulocyte differentiation which, in turn, led to significantly increased OCT-1 activity (P=0.024).


CONCLUSIONS
These studies suggest that the predictive OCT-1 activity in patient mononuclear cells is strongly related to cell lineage, particularly the presence of neutrophils in the peripheral blood. Furthermore, BCR-ABL expression is unlikely to directly influence OCT-1 activity but may have an indirect role by enhancing granulocyte differentiation.
Engler
Jane R
JR
Department of Haematology, SA Pathology (RAH Campus), Frome Road, Adelaide. Australia.
Zannettino
Andrew C W
AC
Bailey
Charles G
CG
Rasko
John E J
JE
Hughes
Timothy P
TP
White
Deborah L
DL
D015153:Blotting, Western; D016022:Case-Control Studies; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D027702:Organic Cation Transporter 1; D012333:RNA, Messenger; D016044:Fusion Proteins, bcr-abl