Expression Profiling of Ribosome Biogenesis Factors Reveals Nucleolin as a Novel Potential Marker to Predict Outcome in AML Patients

PLoS One. 2017 Jan 19;12(1):e0170160. doi: 10.1371/journal.pone.0170160. eCollection 2017.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease. Prognosis is mainly influenced by patient age at diagnosis and cytogenetic alterations, two of the main factors currently used in AML patient risk stratification. However, additional criteria are required to improve the current risk classification and better adapt patient care. In neoplastic cells, ribosome biogenesis is increased to sustain the high proliferation rate and ribosome composition is altered to modulate specific gene expression driving tumorigenesis. Here, we investigated the usage of ribosome biogenesis factors as clinical markers in adult patients with AML. We showed that nucleoli, the nucleus compartments where ribosome production takes place, are modified in AML by analyzing a panel of AML and healthy donor cells using immunofluorescence staining. Using four AML series, including the TCGA dataset, altogether representing a total of about 270 samples, we showed that not all factors involved in ribosome biogenesis have clinical values although ribosome biogenesis is increased in AML. Interestingly, we identified the regulator of ribosome production nucleolin (NCL) as over-expressed in AML blasts. Moreover, we found in two series that high NCL mRNA expression level was associated with a poor overall survival, particular in elderly patients. Multivariate analyses taking into account age and cytogenetic risk indicated that NCL expression in blast cells is an independent marker of reduced survival. Our study identifies NCL as a potential novel prognostic factor in AML. Altogether, our results suggest that the ribosome biogenesis pathway may be of interest as clinical markers in AML.

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Profiling
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics
  • Nucleolin
  • Phosphoproteins / genetics*
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • RNA-Binding Proteins / genetics*
  • Ribosomes / genetics
  • Ribosomes / metabolism
  • Up-Regulation
  • Young Adult

Substances

  • Biomarkers, Tumor
  • NOP56 protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA-Binding Proteins

Grants and funding

This study was supported by Ligue Nationale Contre le Cancer Comité Rhône (n°13-763C, 2014), Comité Allier (2016) and Comité Saône-et-Loire (2016), CNRS, INSERM, Université Claude Bernard Lyon-1, Centre Léon Bérard. VM was a recipient of a postdoctoral fellowship from Centre Léon Bérard. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.