Open AccessNormal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact
Author(s) -
Anna Amanda Schönherz,
Julie Støve Bødker,
Alexander Schmitz,
Rasmus Froberg Brøndum,
Lasse Hjort Jakobsen,
Anne Stidsholt Roug,
Marianne Tang Severinsen,
Tarec Christoffer ElGalaly,
Paw Jensen,
Hans Erik Johnsen,
Martin Bøgsted,
Karen Dybkær
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0229593
Subject(s) - cebpa , biology , myeloid , npm1 , cd38 , cancer research , cd34 , haematopoiesis , progenitor cell , immunology , stem cell , gene , genetics , mutation , karyotype , chromosome
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 m yeloid progenitor cell subset- a ssociated g ene s ignatures (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.