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Patient-tailored analysis of minimal residual disease in acute myeloid leukemia using next generation sequencing.

Journal article
Authors Erik Malmberg
Sara Ståhlman
Anna Rehammar
Tore Samuelsson
Sofie J. Alm
Erik Kristiansson
Jonas Abrahamsson
Hege Garelius
Louise Pettersson
Mats Ehinger
Lars Palmqvist
Linda Fogelstrand
Published in European journal of haematology
Volume 98
Issue 1
Pages 26–37
ISSN 1600-0609
Publication year 2017
Published at Department of Mathematical Sciences
Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Clinical Sciences, Department of Pediatrics
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 26–37
Language en
Links dx.doi.org/10.1111/ejh.12780
Keywords acute myeloid leukemia; minimal residual disease; massively parallel sequencing
Subject categories Pediatrics

Abstract

Next generation sequencing techniques have revealed that leukemic cells in acute myeloid leukemia often are characterized by a limited number of somatic mutations. These mutations can be the basis for detection of leukemic cells in follow-up samples. The aim of this study was to identify leukemia-specific mutations in cells from patients with acute myeloid leukemia and to use these mutations as markers for minimal residual disease. Leukemic cells and normal lymphocytes were simultaneously isolated at diagnosis from 17 patients with acute myeloid leukemia using fluorescence activated cell sorting. Exome sequencing of these cells identified 240 leukemia-specific single nucleotide variations and 22 small insertions and deletions. Based on estimated allele frequencies and their accuracies, 191 of these mutations qualified as candidates for minimal residual disease analysis. Targeted deep sequencing with a significance threshold of 0.027% for single nucleotide variations and 0.006% for NPM1 type A mutation was developed for quantification of minimal residual disease. When tested on follow-up samples from a patient with acute myeloid leukemia, targeted deep sequencing of single nucleotide variations as well as NPM1 was more sensitive than minimal residual disease quantification with multiparameter flow cytometry. In conclusion, we here describe how exome sequencing can be used for identification of leukemia-specific mutations in samples already at diagnosis of acute myeloid leukemia. We also show that targeted deep sequencing of such mutations, including single nucleotide variations, can be used for high-sensitivity quantification of minimal residual disease in a patient-tailored manner. This article is protected by copyright. All rights reserved.

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