Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.

Acute myeloid leukaemia (AML) is characterised by phenotypic heterogeneity, which we hypothesise is a consequence of deregulated differentiation with transcriptional reminiscence of the normal compartment or cell-of-origin. Here, we propose a classification system based on normal myeloid progenitor...

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Autores principales:	Anna A Schönherz, Julie Støve Bødker, Alexander Schmitz, Rasmus Froberg Brøndum, Lasse Hjort Jakobsen, Anne Stidsholt Roug, Marianne T Severinsen, Tarec C El-Galaly, Paw Jensen, Hans Erik Johnsen, Martin Bøgsted, Karen Dybkær
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9d6f994c235e49a98003993006237fd0
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spelling	oai:doaj.org-article:9d6f994c235e49a98003993006237fd02021-12-02T20:15:51ZNormal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.1932-620310.1371/journal.pone.0229593https://doaj.org/article/9d6f994c235e49a98003993006237fd02020-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0229593https://doaj.org/toc/1932-6203Acute myeloid leukaemia (AML) is characterised by phenotypic heterogeneity, which we hypothesise is a consequence of deregulated differentiation with transcriptional reminiscence of the normal compartment or cell-of-origin. Here, we propose a classification system based on normal myeloid progenitor cell subset-associated gene signatures (MAGS) for individual assignments of AML subtypes. We generated a MAGS classifier including the progenitor compartments CD34+/CD38- for haematopoietic stem cells (HSCs), CD34+/CD38+/CD45RA- for megakaryocyte-erythroid progenitors (MEPs), and CD34+/CD38+/CD45RA+ for granulocytic-monocytic progenitors (GMPs) using regularised multinomial regression with three discrete outcomes and an elastic net penalty. The regularisation parameters were chosen by cross-validation, and MAGS assignment accuracy was validated in an independent data set (N = 38; accuracy = 0.79) of sorted normal myeloid subpopulations. The prognostic value of MAGS assignment was studied in two clinical cohorts (TCGA: N = 171; GSE6891: N = 520) and had a significant prognostic impact. Furthermore, multivariate Cox regression analysis using the MAGS subtype, FAB subtype, cytogenetics, molecular genetics, and age as explanatory variables showed independent prognostic value. Molecular characterisation of subtypes by differential gene expression analysis, gene set enrichment analysis, and mutation patterns indicated reduced proliferation and overrepresentation of RUNX1 and IDH2 mutations in the HSC subtype; increased proliferation and overrepresentation of CEBPA mutations in the MEP subtype; and innate immune activation and overrepresentation of WT1 mutations in the GMP subtype. We present a differentiation-dependent classification system for AML subtypes with distinct pathogenetic and prognostic importance that can help identify candidates poorly responding to combination chemotherapy and potentially guide alternative treatments.Anna A SchönherzJulie Støve BødkerAlexander SchmitzRasmus Froberg BrøndumLasse Hjort JakobsenAnne Stidsholt RougMarianne T SeverinsenTarec C El-GalalyPaw JensenHans Erik JohnsenMartin BøgstedKaren DybkærPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 15, Iss 4, p e0229593 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna A Schönherz Julie Støve Bødker Alexander Schmitz Rasmus Froberg Brøndum Lasse Hjort Jakobsen Anne Stidsholt Roug Marianne T Severinsen Tarec C El-Galaly Paw Jensen Hans Erik Johnsen Martin Bøgsted Karen Dybkær Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
description	Acute myeloid leukaemia (AML) is characterised by phenotypic heterogeneity, which we hypothesise is a consequence of deregulated differentiation with transcriptional reminiscence of the normal compartment or cell-of-origin. Here, we propose a classification system based on normal myeloid progenitor cell subset-associated gene signatures (MAGS) for individual assignments of AML subtypes. We generated a MAGS classifier including the progenitor compartments CD34+/CD38- for haematopoietic stem cells (HSCs), CD34+/CD38+/CD45RA- for megakaryocyte-erythroid progenitors (MEPs), and CD34+/CD38+/CD45RA+ for granulocytic-monocytic progenitors (GMPs) using regularised multinomial regression with three discrete outcomes and an elastic net penalty. The regularisation parameters were chosen by cross-validation, and MAGS assignment accuracy was validated in an independent data set (N = 38; accuracy = 0.79) of sorted normal myeloid subpopulations. The prognostic value of MAGS assignment was studied in two clinical cohorts (TCGA: N = 171; GSE6891: N = 520) and had a significant prognostic impact. Furthermore, multivariate Cox regression analysis using the MAGS subtype, FAB subtype, cytogenetics, molecular genetics, and age as explanatory variables showed independent prognostic value. Molecular characterisation of subtypes by differential gene expression analysis, gene set enrichment analysis, and mutation patterns indicated reduced proliferation and overrepresentation of RUNX1 and IDH2 mutations in the HSC subtype; increased proliferation and overrepresentation of CEBPA mutations in the MEP subtype; and innate immune activation and overrepresentation of WT1 mutations in the GMP subtype. We present a differentiation-dependent classification system for AML subtypes with distinct pathogenetic and prognostic importance that can help identify candidates poorly responding to combination chemotherapy and potentially guide alternative treatments.
format	article
author	Anna A Schönherz Julie Støve Bødker Alexander Schmitz Rasmus Froberg Brøndum Lasse Hjort Jakobsen Anne Stidsholt Roug Marianne T Severinsen Tarec C El-Galaly Paw Jensen Hans Erik Johnsen Martin Bøgsted Karen Dybkær
author_facet	Anna A Schönherz Julie Støve Bødker Alexander Schmitz Rasmus Froberg Brøndum Lasse Hjort Jakobsen Anne Stidsholt Roug Marianne T Severinsen Tarec C El-Galaly Paw Jensen Hans Erik Johnsen Martin Bøgsted Karen Dybkær
author_sort	Anna A Schönherz
title	Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
title_short	Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
title_full	Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
title_fullStr	Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
title_full_unstemmed	Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
title_sort	normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/9d6f994c235e49a98003993006237fd0
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Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.

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