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The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age
Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencin...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Lippincott Williams & Wilkins
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461941/ https://www.ncbi.nlm.nih.gov/pubmed/37645423 http://dx.doi.org/10.1097/HS9.0000000000000939 |
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author | Beder, Thomas Hansen, Björn-Thore Hartmann, Alina M. Zimmermann, Johannes Amelunxen, Eric Wolgast, Nadine Walter, Wencke Zaliova, Marketa Antić, Željko Chouvarine, Philippe Bartsch, Lorenz Barz, Malwine J. Bultmann, Miriam Horns, Johanna Bendig, Sonja Kässens, Jan Kaleta, Christoph Cario, Gunnar Schrappe, Martin Neumann, Martin Gökbuget, Nicola Bergmann, Anke Katharina Trka, Jan Haferlach, Claudia Brüggemann, Monika Baldus, Claudia D. Bastian, Lorenz |
author_facet | Beder, Thomas Hansen, Björn-Thore Hartmann, Alina M. Zimmermann, Johannes Amelunxen, Eric Wolgast, Nadine Walter, Wencke Zaliova, Marketa Antić, Željko Chouvarine, Philippe Bartsch, Lorenz Barz, Malwine J. Bultmann, Miriam Horns, Johanna Bendig, Sonja Kässens, Jan Kaleta, Christoph Cario, Gunnar Schrappe, Martin Neumann, Martin Gökbuget, Nicola Bergmann, Anke Katharina Trka, Jan Haferlach, Claudia Brüggemann, Monika Baldus, Claudia D. Bastian, Lorenz |
author_sort | Beder, Thomas |
collection | PubMed |
description | Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning-based classifier using RNA-Seq gene expression data to allocate BCP-ALL samples to all 21 gene expression-defined molecular subtypes. Trained on n = 1869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n = 1018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High-confidence predictions were achieved in 83.7% of samples with 98.9% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel driver candidates in previously unassigned samples. Additional modules provided predictions of samples blast counts, patient’s sex, and immunophenotype, allowing the imputation in cases where these information are missing. We established a novel RNA-Seq reference of human B-lymphopoiesis using 7 FACS-sorted progenitor stages from healthy bone marrow donors. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory. This identified shared proximity patterns of BCP-ALL subtypes to normal lymphopoiesis stages, extending immunophenotypic classifications with a novel framework for developmental comparisons of BCP-ALL. ALLCatchR enables RNA-Seq routine application for BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocation and novel insights into underlying developmental trajectories. |
format | Online Article Text |
id | pubmed-10461941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-104619412023-08-29 The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age Beder, Thomas Hansen, Björn-Thore Hartmann, Alina M. Zimmermann, Johannes Amelunxen, Eric Wolgast, Nadine Walter, Wencke Zaliova, Marketa Antić, Željko Chouvarine, Philippe Bartsch, Lorenz Barz, Malwine J. Bultmann, Miriam Horns, Johanna Bendig, Sonja Kässens, Jan Kaleta, Christoph Cario, Gunnar Schrappe, Martin Neumann, Martin Gökbuget, Nicola Bergmann, Anke Katharina Trka, Jan Haferlach, Claudia Brüggemann, Monika Baldus, Claudia D. Bastian, Lorenz Hemasphere Article Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning-based classifier using RNA-Seq gene expression data to allocate BCP-ALL samples to all 21 gene expression-defined molecular subtypes. Trained on n = 1869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n = 1018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High-confidence predictions were achieved in 83.7% of samples with 98.9% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel driver candidates in previously unassigned samples. Additional modules provided predictions of samples blast counts, patient’s sex, and immunophenotype, allowing the imputation in cases where these information are missing. We established a novel RNA-Seq reference of human B-lymphopoiesis using 7 FACS-sorted progenitor stages from healthy bone marrow donors. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory. This identified shared proximity patterns of BCP-ALL subtypes to normal lymphopoiesis stages, extending immunophenotypic classifications with a novel framework for developmental comparisons of BCP-ALL. ALLCatchR enables RNA-Seq routine application for BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocation and novel insights into underlying developmental trajectories. Lippincott Williams & Wilkins 2023-08-25 /pmc/articles/PMC10461941/ /pubmed/37645423 http://dx.doi.org/10.1097/HS9.0000000000000939 Text en Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) (https://creativecommons.org/licenses/by-nc/4.0/) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. |
spellingShingle | Article Beder, Thomas Hansen, Björn-Thore Hartmann, Alina M. Zimmermann, Johannes Amelunxen, Eric Wolgast, Nadine Walter, Wencke Zaliova, Marketa Antić, Željko Chouvarine, Philippe Bartsch, Lorenz Barz, Malwine J. Bultmann, Miriam Horns, Johanna Bendig, Sonja Kässens, Jan Kaleta, Christoph Cario, Gunnar Schrappe, Martin Neumann, Martin Gökbuget, Nicola Bergmann, Anke Katharina Trka, Jan Haferlach, Claudia Brüggemann, Monika Baldus, Claudia D. Bastian, Lorenz The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age |
title | The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age |
title_full | The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age |
title_fullStr | The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age |
title_full_unstemmed | The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age |
title_short | The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age |
title_sort | gene expression classifier allcatchr identifies b-cell precursor all subtypes and underlying developmental trajectories across age |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461941/ https://www.ncbi.nlm.nih.gov/pubmed/37645423 http://dx.doi.org/10.1097/HS9.0000000000000939 |
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