Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing

Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transc...

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Bibliographic Details
Published in:Leukemia 2021-01, Vol.35 (1), p.47-61
Main Authors: Arindrarto, Wibowo, Borràs, Daniel M, de Groen, Ruben A L, van den Berg, Redmar R, Locher, Irene J, van Diessen, Saskia A M E, van der Holst, Rosalie, van der Meijden, Edith D, Honders, M Willy, de Leeuw, Rick H, Verlaat, Wina, Jedema, Inge, Kroes, Wilma G M, Knijnenburg, Jeroen, van Wezel, Tom, Vermaat, Joost S P, Valk, Peter J M, Janssen, Bart, de Knijff, Peter, van Bergen, Cornelis A M, van den Akker, Erik B, Hoen, Peter A C 't, Kiełbasa, Szymon M, Laros, Jeroen F J, Griffioen, Marieke, Veelken, Hendrik
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Algorithms
Bioinformatics
Biomarkers, Tumor
Computational Biology - methods
Diagnostic systems
Female
Gene expression
Gene Expression Profiling - methods
Gene Expression Regulation, Leukemic
Gene sequencing
Genes
Genetic Variation
Genomics - methods
Genotype
Health aspects
Humans
Identification and classification
Leukemia
Leukemia, Myeloid, Acute - diagnosis
Leukemia, Myeloid, Acute - genetics
Male
Methods
Molecular Diagnostic Techniques
Mutation
Myeloid leukemia
Oncogene Proteins, Fusion
Prognosis
Reproducibility of Results
Reproduction (copying)
Ribonucleic acid
Risk assessment
RNA
RNA sequencing
Sensitivity
Transcriptome
Transcriptomes
Transcriptomics
Whole Exome Sequencing - methods
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Description
Summary:Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-020-0762-8