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

• Published in: PloS one Vol. 15; no. 4; p. e0229593
• Main Authors: Schönherz, Anna A, Bødker, Julie Støve, Schmitz, Alexander, Brøndum, Rasmus Froberg, Jakobsen, Lasse Hjort, Roug, Anne Stidsholt, Severinsen, Marianne T, El-Galaly, Tarec C, Jensen, Paw, Johnsen, Hans Erik, Bøgsted, Martin, Dybkær, Karen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2020; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Biology and Life Sciences; Bone marrow; Cancer; CD34 antigen; CD38 antigen; CD45RA antigen; Chemotherapy; Classification; Clinical medicine; Cytogenetics; Datasets; Deregulation; Differentiation; Gene expression; Gene set enrichment analysis; Genetics; Genomes; Hematology; Hematopoietic stem cells; Heterogeneity; Immune response; Independent variables; Leukemia; Medical prognosis; Medical research; Medicine; Monocytes; Mutation; Physical Sciences; Progenitor cells; Quantitative genetics; Regression analysis; Regularization; Research and Analysis Methods; Runx1 protein; Signatures; Statistical analysis; Stem cells; Subpopulations; Transcription; Denmark; Aarhus Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0229593

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.