Multidrug-related protein 1 (MRP1) polymorphisms rs129081, rs212090, and rs212091 predict survival in normal karyotype acute myeloid leukemia

Desiree Kunadt,Maria Schmiedgen,Heidi Altmann,Markus Schaich,Claudia Dill,Michael Kramer,Christoph Röllig,Friedrich Stölzel,Christian Dransfeld,Ulrich Mahlknecht,Martin Bornhäuser

doi:10.1007/s00277-020-04163-7

Abstract

Resistant disease is still a main obstacle in acute myeloid leukemia (AML) treatment. Therefore, individual genetic variations affecting therapy response are gaining increasing importance. Both SNPs and ABC transporter genes could already be associated with drug resistance. Here, we report allelic variants of MRP1 (ABCC1) SNPs rs129081, rs212090, and rs212091 with significant influences on survival in AML patients. DNA was extracted from bone marrow samples (n = 160) at diagnosis. Genotyping 48 SNPs within seven different ABC transporter genes using real-time PCR revealed rs129081 GG variant with a significant higher OS (p = 0.035) and DFS (p = 0.01). Comparing TT and AA rs212090 variants showed significant influences on DFS (p = 0.021). SNP rs212091 GG expression was associated with worse OS (p = 0.006) and a significant difference in DFS between alleles GG and AA (p = 0.018). The multivariable models confirmed a significant influence on OS for rs212091 (AA HR = 0.296, 95% CI 0.113–0.774, p = 0.013 and GG p = 0.044). Rs129081 variant CG, TT of rs212090, AA, and AG of rs212091 demonstrated significant impact on DFS (p = 0.024, p = 0.029, p = 0.017, and p = 0.042, respectively). This analysis demonstrates a significant influence of MRP1 SNPs on survival in AML. As they were not associated to prognostic characteristics, we suggest these SNPs to be independent prognostic markers for AML.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of undifferentiated myeloid blasts requiring rapid induction chemotherapy to induce a remission
Patients carrying the homozygous rs129081 GG-single nucleotide polymorphisms (SNPs) (n = 65) had a significant higher 5-year-Overall survival (OS) and 5-year-disease-free survival (DFS), compared to the homozygous wild type CC (n = 27) and heterozygous CG (n = 68) patients (OS: GG 68% [95% confidence interval (CI) 55–80%] vs. CC 40% [95% CI 18–61%] vs. CG 64% [95% CI 52– 75%], p = 0.035; DFS: GG 64% [95% CI 50–77%] vs. CC 35% [95% CI 16–53%] vs. CG 50% [95% CI 38–62%], p = 0.01) in univariate analysis, Figs. 1 and 2
These results did not have a significant impact on OS in multivariable analysis (Table 2), heterozygous CG demonstrated a significant impact on DFS in multivariable analysis (p = 0.024), while the other allele variants of rs129081 had no independent influence on DFS (Table 3)

Summary

Introduction

Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of undifferentiated myeloid blasts requiring rapid induction chemotherapy to induce a remission. Approximately 75% of patients achieve complete remission (CR) after induction treatment consisting of cytarabine (100 mg/m2, days 1–7) and daunorubicin (60 mg/ m2, on three consecutive days), two-thirds of AML patients under the age of 60 relapse after successful induction chemotherapy, with an even higher rate in older patients [1,2,3]. Drug resistance affecting standard chemotherapeutic compounds in AML results in induction failure or relapse. Very often relapse presents with a highly aggressive AML clone insensitive to salvage chemotherapy with the urgent need of intensified treatment and more invasive procedures like allogeneic stem cell transplantation, far the only available curative option for these patients. Molecular mechanisms causing therapy failure leading to inferior prognosis of AML patients are still incompletely

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