ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients.
OBJECTIVE
The classical multidrug resistance (MDR) gene MDR1 (ABCB1) encodes for the drug efflux pump P-glycoprotein (P-gp). P-gp expression is an adverse prognostic factor for treatment outcome in acute myeloid leukemia (AML) and is more frequently observed in older patients. Single-nucleotide polymorphisms of the ABCB1 gene, C1236T, G2677T, and C3435T, have been associated with altered drug metabolism and treatment outcome. We prospectively determined these single-nucleotide polymorphisms in AML blasts in a cohort of patients aged 60 years or older with AML and evaluated their relevance with regard to P-gp function and expression, ABCB1 messenger ribonucleic acid (mRNA) expression, and clinical outcome.


METHODS
We have analyzed purified bone marrow-derived leukemic blasts, obtained at diagnosis, in 150 patients who were treated within a multicenter, randomized, phase 3 trial of elderly patients with AML. The significance of the allelic ABCB1 variants of C1236T, G2677T, and C3435T was evaluated with respect to P-gp expression and function in leukemic blasts and ABCB1 mRNA expression levels, and these values were correlated with treatment outcome.


RESULTS
P-gp function and expression in leukemic blasts and ABCB1 mRNA levels in patients with AML did not vary significantly among any of the allelic variants of ABCB1. None of these allelic variations predicted a difference in complete response rate and survival endpoints.


CONCLUSIONS
In AML patients aged 60 years or older, allelic ABCB1 variations of C1236T, G2677T, or C3435T are not associated with altered P-gp function or with MDR1 expression at the transcriptional or translational level in leukemic blasts, and they do not significantly affect clinical prognosis.
van der Holt
Bronno
B
Department of Trials & Statistics-HOVON (Dutch-Belgian Hemato-Oncology Cooperative Group) Data Center, Erasmus MC-Daniel den Hoed Cancer Center and Sophia Children's Hospital, Rotterdam, The Netherlands. b.vanderholt@erasmusmc.nl
Van den Heuvel-Eibrink
Marry M
MM
Van Schaik
Ron H N
RH
van der Heiden
Ilse P
IP
Wiemer
Erik A C
EA
Vossebeld
Paula J M
PJ
Löwenberg
Bob
B
Sonneveld
Pieter
P
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D012333:RNA, Messenger