Identification of let-7a-2-3p or/and miR-188-5p as Prognostic Biomarkers in Cytogenetically Normal Acute Myeloid Leukemia

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Abstract

Cytogenetically normal acute myeloid leukemia (CN-AML) is the largest and most heterogeneous AML subgroup. It lacks sensitive and specific biomarkers. Emerging evidences have suggested that microRNAs are involved in the pathogenesis of various leukemias. This paper evaluated the association between microRNA expression and prognostic outcome for CN-AML, based on the RNA/microRNA sequencing data of CN-AML patients. High let-7a-2-3p expression and low miR-188-5p expression were identified to be significantly associated with longer overall survival (OS) and event free survival (EFS) for CN-AML, independently or in a combined way. Their prognostic values were further confirmed in European Leukemia Net (ELN) genetic categories. Also, in multivariable analysis with other known risk factors, high let-7a-2-3p and low miR-188-5p expression remained to be associated with longer OS and EFS. In addition, the prognostic value of these two microRNAs was confirmed in patients who received hematopoietic stem cell transplantation (HSCT). To gain more biological insights of the underlying mechanisms, we derived the genome-wide differential gene/microRNA signatures associated with the expression of let-7a-2-3p and miR-188-5p. Several common microRNA signatures indicating favorable outcome in previous studies were up-regulated in both high let-7a-2-3p expressers and low miR-188-5p expressers, including miR-135a, miR-335 and miR-125b and all members of miR-181 family. Additionally, common up-regulated genes included FOSB, IGJ, SNORD50A and ZNF502, and FOSB was a known favorable signature in AML. These common signatures further confirmed the underlying common mechanisms for these two microRNAs value as favorable prognostic biomarkers. We concluded that high let-7a-2-3p and low miR-188-5p expression could be potentially used as favorably prognostic biomarkers independently or in a combined way in CN-AML patients, whether they received HSCT or not.

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Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

Brunangelo Falini, Cristina Mecucci, Enrico Tiacci … (2005)

Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein. We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease. Cytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells. Cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy. Copyright 2005 Massachusetts Medical Society.

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Prognostically useful gene-expression profiles in acute myeloid leukemia.

Peter J. M. Valk, Roel G. W. Verhaak, M Beijen … (2004)

In patients with acute myeloid leukemia (AML) a combination of methods must be used to classify the disease, make therapeutic decisions, and determine the prognosis. However, this combined approach provides correct therapeutic and prognostic information in only 50 percent of cases. We determined the gene-expression profiles in samples of peripheral blood or bone marrow from 285 patients with AML using Affymetrix U133A GeneChips containing approximately 13,000 unique genes or expression-signature tags. Data analyses were carried out with Omniviz, significance analysis of microarrays, and prediction analysis of microarrays software. Statistical analyses were performed to determine the prognostic significance of cases of AML with specific molecular signatures. Unsupervised cluster analyses identified 16 groups of patients with AML on the basis of molecular signatures. We identified the genes that defined these clusters and determined the minimal numbers of genes needed to identify prognostically important clusters with a high degree of accuracy. The clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We identified several novel clusters, some consisting of specimens with normal karyotypes. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome. Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis. Copyright 2004 Massachusetts Medical Society

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MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia.

Ramiro Garzon, Stefano Volinia, Chang-Gong Liu … (2008)

MicroRNAs (miRNAs) are small RNAs of 19 to 25 nucleotides that are negative regulators of gene expression. To determine whether miRNAs are associated with cytogenetic abnormalities and clinical features in acute myeloid leukemia (AML), we evaluated the miRNA expression of CD34(+) cells and 122 untreated adult AML cases using a microarray platform. After background subtraction and normalization using a set of housekeeping genes, data were analyzed using Significance Analysis of Microarrays. An independent set of 60 untreated AML patients was used to validate the outcome signatures using real-time polymerase chain reaction. We identified several miRNAs differentially expressed between CD34(+) normal cells and the AML samples. miRNA expression was also closely associated with selected cytogenetic and molecular abnormalities, such as t(11q23), isolated trisomy 8, and FLT3-ITD mutations. Furthermore, patients with high expression of miR-191 and miR-199a had significantly worse overall and event-free survival than AML patients with low expression (overall survival: miR-191, P = .03; and miR-199a, P = .001, Cox regression). In conclusion, miRNA expression in AML is closely associated with cytogenetics and FLT3-ITD mutations. A small subset of miRNAs is correlated with survival.

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Author and article information

Contributors

Ken Mills: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 3 February 2015

Publication date Collection: 2015

Volume: 10

Issue: 2

Electronic Location Identifier: e0118099

Affiliations

[1 ]Medical Engineering Division, Hainan Branch, Chinese PLA General Hospital, Sanya, Hainan, China

[2 ]Medical Engineering Support Center, Chinese PLA General Hospital, Beijing, China

[3 ]Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, China

[4 ]Department of Hematology, Chinese PLA General Hospital, Beijing, China

Queen’s University Belfast, UNITED KINGDOM

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SJL WWD FL YL. Performed the experiments: SJL FL. Analyzed the data: SJL FL LYH. Contributed reagents/materials/analysis tools: SJL FL. Wrote the paper: SJL FL LYH.

‡ These authors contributed equally to this work.

* E-mail: wangwd301@ 123456126.com (WWD); chunhuiliyu@ 123456yahoo.com (YL)

Article

Publisher ID: PONE-D-14-43697

DOI: 10.1371/journal.pone.0118099

PMC ID: 4315415

PubMed ID: 25646775

SO-VID: 5b1b75a5-a503-49bb-9357-c698fa1a09c8

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 2 October 2014

Date accepted : 5 January 2015

Page count

Figures: 5, Tables: 4, Pages: 14

Funding

The work was supported by grants from the National Natural Science Foundation of China (61372047) and the National High-tech R&D Program of China (2013BAI03B04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All data is available from TCGA data portal. ( https://tcga-data.nci.nih.gov/docs/publications/laml_2012/)

Identification of let-7a-2-3p or/and miR-188-5p as Prognostic Biomarkers in Cytogenetically Normal Acute Myeloid Leukemia

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Most cited references 33

Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

Prognostically useful gene-expression profiles in acute myeloid leukemia.

MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia.

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