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

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 + /CD38for haematopoietic stem cells (HSCs), CD34 + / CD38 + /CD45RAfor 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 differentiationdependent 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.

Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment

“…Specific surface biomarkers characterize the subpopulations of AML cells. For example, leukemic stem cells are characterized by CD34 + /CD38 − surface markers, megakaryocyte-erythroid progenitors (MEPs) are characterized by CD34 + /CD38 + /CD45RA − surface markers, and granulocytic-monocytic progenitors (GMPs) are characterized by CD34 + /CD38 + /CD45RA + surface markers [5][6][7]. Aberrant multipotent progenitor cells give rise to myeloid lineage-committed cells showing further phenotypical as well as functional changes.…”

“…Gene mutations precipitate key events in AML pathogenesis [11,12]. The gene mutations common in AML are well documented elsewhere [7] and some of the key genetic factors are summarized in Table 1. Class I mutations lead to uncontrolled cellular proliferation and evasion of apoptosis and include mutation conferring constitutive activity to tyrosine kinases or dysregulation of downstream signaling molecules (in genes such as BCR-ABL, LLT3, c-KIT, and RAS) [13].…”