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

Malmberg, Erik B R; Ståhlman, Sara; Rehammar, Anna; Samuelsson, Tore; Alm, Sofie J.; Kristiansson, Erik; Abrahamsson, Jonas; Garelius, Hege; Pettersson, Louise LU and Ehinger, Mats LU , et al. (2017) In European Journal of Haematology 98(1). p.26-37
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 the 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... (More)

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 the 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.

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publication status
published
subject
keywords
Acute myeloid leukemia, Massively parallel sequencing, Minimal residual disease
in
European Journal of Haematology
volume
98
issue
1
pages
26 - 37
publisher
Wiley-Blackwell
external identifiers
  • Scopus:84973867696
ISSN
0902-4441
DOI
10.1111/ejh.12780
language
English
LU publication?
yes
id
45083c09-6f3e-4dd6-98b9-15bae17801b9
date added to LUP
2016-07-13 10:19:21
date last changed
2017-01-13 16:39:09
@article{45083c09-6f3e-4dd6-98b9-15bae17801b9,
  abstract     = {<p>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 the 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.</p>},
  author       = {Malmberg, Erik B R and Ståhlman, Sara and Rehammar, Anna and Samuelsson, Tore and Alm, Sofie J. and Kristiansson, Erik and Abrahamsson, Jonas and Garelius, Hege and Pettersson, Louise and Ehinger, Mats and Palmqvist, Lars and Fogelstrand, Linda},
  issn         = {0902-4441},
  keyword      = {Acute myeloid leukemia,Massively parallel sequencing,Minimal residual disease},
  language     = {eng},
  number       = {1},
  pages        = {26--37},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Haematology},
  title        = {Patient-tailored analysis of minimal residual disease in acute myeloid leukemia using next-generation sequencing},
  url          = {http://dx.doi.org/10.1111/ejh.12780},
  volume       = {98},
  year         = {2017},
}