A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia

Academic Article

Abstract

  • Acte myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a 'core enriched' (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CE high) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CE high patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CE low patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CE high status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CE high patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML. © 2013 Macmillan Publishers Limited All rights reserved.
  • Published In

  • Leukemia  Journal
  • Digital Object Identifier (doi)

    Author List

  • Metzeler KH; Maharry K; Kohlschmidt J; Volinia S; Mrózek K; Becker H; Nicolet D; Whitman SP; Mendler JH; Schwind S
  • Start Page

  • 2023
  • End Page

  • 2031
  • Volume

  • 27
  • Issue

  • 10