title: Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype.
abstract: Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0·017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0·039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.
authors.affiliation: Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jakobsen Falk
authors.forename: Anna
authors.initials: A
authors.lastname: Fyrberg
authors.forename: Esbjörn
authors.initials: E
authors.lastname: Paul
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.forename: Monica
authors.initials: M
authors.lastname: Hermanson
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.forename: Lars
authors.initials: L
authors.lastname: Palmqvist
authors.forename: Dick
authors.initials: D
authors.lastname: Stockelberg
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wei
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: ABCB1; FLT3; acute myeloid leukaemia; anthracyclines; single nucleotide polymorphism