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

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

Virginie Marcel  1   2   3 , Frédéric Catez  1   2   3 , Caroline M Berger  1   2   3 , Emeline Perrial  1   2   4 , Adriana Plesa  5 , Xavier Thomas  6 , Eve Mattei  5 , Sandrine Hayette  5 , Pierre Saintigny  1   2   7 , Philippe Bouvet  1   2   3   8 , Jean-Jacques Diaz  1   2   3 , Charles Dumontet  1   2   4
Affiliations

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

Virginie Marcel et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Increase in nucleoli number and size in AML patients.
(A) Immunofluorescence staining of nucleolar fibrillarin (FBL) and nucleolin (NCL) in healthy donors (control) and AML patients bone marrow smears. FBL (green) and NCL (red) patterns are shown individually in top and middle images, and merge image with nuclei staining (blue) is shown in the bottom. Images were collected using confocal microscope (scale = 10μm). (B) Number of nucleoli per cell, quantified by image analysis from 4 control and 6 AML smears. Box and whisker plots represents median (middle horizontal bar), inter-quartile range (bottom and top of the box) and minimal/maximal values (bottom and top of the whiskers) of nucleoli number per cell. Representative panels of images used to perform these image analyses for each individual are shown in S2 Fig. n: number of samples; *: P<0.05.
Fig 2
Fig 2. Over-expression of NCL and NOP56, two ribosome biogenesis factors, in AML blasts.
(A-B) Mean comparisons of NCL (A) and NOP56 (B) gene expression between controls and AML patients were compared using the Mann-Whitney test. Log2 (Relative RNA levels) were determined using high-throughput qPCR in series 2. Graphs represents median (middle horizontal bar) and inter-quartile range (bottom and top bars) calculated on the log2 (Relative RNA levels) of each individual sample (grey dot). n: number of samples; ***: P<0.0001.
Fig 3
Fig 3. Overall survival of AML patients related to NCL and NOP56.
(A-B) Kaplan-Meier analysis of overall survival rates (event = death related to AML disease) according to NCL (A) and NOP56 (B) expression at diagnosis in series 3. The data are dichotomized at the 75% percentile value into high and low mRNA level groups. n: number of samples; *: P<0.05.
Fig 4
Fig 4. Overall survival of AML patients related to NCL expression depending upon age in the TCGA series.
(A-C) Kaplan-Meier analysis of overall survival rates (event = death related to AML disease) according to NCL expression in series TCGA for all AML patients (A), AML patients younger than 60 years (B) or AML patients older than 60 years (C). The data are dichotomized at the 75% percentile value into high and low mRNA level groups. n: number of samples; *: P<0.05.
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References

    1. Chen S-J, Shen Y, Chen Z. A panoramic view of acute myeloid leukemia. Nat Genet. 2013;45: 586–587. 10.1038/ng.2651 - DOI - PubMed
    1. Liersch R, Müller-Tidow C, Berdel WE, Krug U. Prognostic factors for acute myeloid leukaemia in adults—biological significance and clinical use. Br J Haematol. 2014;165: 17–38. 10.1111/bjh.12750 - DOI - PubMed
    1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127: 2391–2405. 10.1182/blood-2016-03-643544 - DOI - PubMed
    1. Mrozek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia. Journal of Clinical Oncology. 2012;30: 4515–4523. 10.1200/JCO.2012.43.4738 - DOI - PMC - PubMed
    1. Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B, et al. Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic Risk Classification of the European LeukemiaNet Recommendations: Evaluation of the Proposed Reporting System. Journal of Clinical Oncology. 2011;29: 2758–2765. 10.1200/JCO.2010.32.8500 - DOI - PubMed

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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.