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Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-4450-0333
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
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2013 (English)In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed) Published
Abstract [en]

De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and −451C>T rs532545), 5′-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3′UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and −451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML

Place, publisher, year, edition, pages
John Wiley & Sons, 2013. Vol. 88, no 12, p. 1001-1006
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-98699DOI: 10.1002/ajh.23549ISI: 000327224000125PubMedID: 23873772OAI: oai:DiVA.org:liu-98699DiVA, id: diva2:655527
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2018-12-19
In thesis
1. Prognostic markers in acute myeloid leukemia: A candidate gene approach
Open this publication in new window or tab >>Prognostic markers in acute myeloid leukemia: A candidate gene approach
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The standard treatment of acute myeloid leukemia (AML) consists of induction chemotherapy, most commonly daunorubicin together with the nucleoside analogue cytarabine (Ara-C), followed by consolidation chemotherapy and in selected cases allogenic stem cell transplantation (allo-SCT). Despite a high initial response rate, a considerable proportion of all AML cases eventually suffer from relapse and the five-year overall survival rate in patients >60 years is only around 15%. Based on cytogenetic analysis, patients are divided into low risk, intermediate risk, and high-risk groups. While low risk patients have a high chance of reaching and remaining in remission after standard induction therapy, high-risk patients are likely to suffer from relapse and should be scheduled for allo-SCT when first complete remission is reached. The intermediate risk group consists of normal karyotype (NK) patients and those with karyotypes of uncertain clinical relevance, but the outcomes are heterogeneous. In NKAML patients, risk classification has improved with the addition of molecular markers including FLT3 internal tandem duplications (ITD) and mutations of NPM1 and CEBPA. Despite this development, there is a group of patients lacking reliable prognostic markers and in some cases the outcomes predicted do not match the outcomes observed, highlighting the need for additional markers. ABCB1 encodes a transporter protein responsible for the extrusion of cytotoxic compounds, including daunorubicin, over the cell membrane, and is a known resistance mechanism. Ara-C is subject to both activating and inactivating metabolic enzymes including DCK (activating), CDA and cN-II (inactivating). ABCB1, DCK, CDA and cN-II are all polymorphic, and SNPs affecting enzyme function and/or activity have potential as prognostic markers. In addition, recurrent IDH1/2 mutations lead to the expression of an enzyme with neomorphic activity associated with epigenetic alterations and disturbed differentiation. Mutations as well as a SNP in codon 105 of IDH1 have prognostic implications in AML, although the effects of different IDH mutations have been unclear. The aim of this thesis was to investigate SNPs in ABCB1 and genes associated with Ara-C metabolism, mutations in IDH1/2 and the IDH1 SNP, and their associations with treatment response and survival in AML. We show that the 1236C>T and 2677G>T SNPs in ABCB1 influence in vitro sensitivity towards AML drugs, with corresponding effects on NK-AML patient survival. These survival differences were seen mainly in patients lacking FLT3-ITD, further adding to the risk stratification. In contrast, the CDA SNPs 79A>C and -451C>T appear to influence survival mainly in FLT3-ITD positive cases. In conclusion, the above-mentioned SNPs have the potential to add important information to risk classifications especially in NK-AML patients with the ambiguous FLT3-ITD-/NPM1- or FLT3-ITD+/NPM1+ genotypes. In addition, we have shown that IDH2 R140 mutation is associated with impaired survival in AML, and that the IDH1 codon 105 SNP appears to confer a worse outcome in a subset of intermediate risk patients without FLT3-ITD. With the introduction of next generation sequencing into clinical diagnostics, IDH mutations may not only provide prognostic information but also guide the selection of patients for new drugs targeting the variant enzyme. Our results indicate that in addition to leukemia-specific mutations, constitutional SNPs may prove useful for further individualizing care-taking and should be considered when implementing these new techniques.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 76
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1648
National Category
Hematology
Identifiers
urn:nbn:se:liu:diva-153476 (URN)10.3384/diss.diva-153476 (DOI)9789176851951 (ISBN)
Public defence
2019-01-11, Berzeliussalen, Campus US, Linköping, 09:00 (English)
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Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved

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Jakobsen Falk, IngridFyrberg, AnnaGréen, HenrikLotfi, Kourosh

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