Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia.
OBJECTIVE
Imatinib resistance is major cause of imatinib mesylate (IM) treatment failure in chronic myeloid leukemia (CML) patients. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including amplification and overexpression of the BCR/ABL gene, the tyrosine kinase domain point mutations, and MDR1 gene overexpression.


METHODS
We investigated the impact of 16 single nucleotide polymorphisms (SNP) in five genes potentially associated with pharmacogenetics of IM, namely ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5, cytochrome P450-3A5; SLC22A1, human organic cation transporter 1; and AGP, alpha1-acid glycoprotein. The DNAs from peripheral blood samples in 229 patients were genotyped.


RESULTS
The GG genotype in ABCG2 (rs2231137), AA genotype in CYP3A5 (rs776746), and advanced stage were significantly associated with poor response to IM especially for major or complete cytogenetic response, whereas the GG genotype at SLC22A1 (rs683369) and advanced stage correlated with high rate of loss of response or treatment failure to IM therapy.


CONCLUSIONS
We showed that the treatment outcomes of imatinib therapy could be predicted using a novel, multiple candidate gene approach based on the pharmacogenetics of IM.
Kim
Dong Hwan Dennis
DH
Chronic Myelogenous Leukemia Group, Department of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. drkiim@medimail.co.kr
Sriharsha
Lakshmi
L
Xu
Wei
W
Kamel-Reid
Suzanne
S
Liu
Xiangdong
X
Siminovitch
Katherine
K
Messner
Hans A
HA
Lipton
Jeffrey H
JH
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D050811:Octamer Transcription Factor-1 / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D006023:Glycoproteins; D009363:Neoplasm Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016044:Fusion Proteins, bcr-abl