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

PLoS One. 2020 Apr 23;15(4):e0229593. doi: 10.1371/journal.pone.0229593. eCollection 2020.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / genetics
  • Antigens, CD34 / genetics
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Leukocyte Common Antigens / genetics
  • Male
  • Middle Aged
  • Mutation / genetics
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology
  • Principal Component Analysis
  • Regression Analysis
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • WT1 Proteins / genetics

Substances

  • Antigens, CD34
  • Core Binding Factor Alpha 2 Subunit
  • RUNX1 protein, human
  • WT1 Proteins
  • WT1 protein, human
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • Leukocyte Common Antigens
  • ADP-ribosyl Cyclase 1

Grant support

HEJ, 30-06-2015, Karen Elise Jensen Fonden, http://www.kejfond.dk/. JSB, 27251, Det Obelske Familefond, http://obel.com/. MB, 153-2014-10, Innovationsfonden, https://innovationsfonden.dk The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.