Genome‐wide characterization of lncRNAs in acute myeloid leukemia

&NA; Long noncoding RNAs (lncRNAs) are a large family of noncoding RNAs that play a critical role in various normal bioprocesses as well as tumorigenesis. However, the expression patterns and biological functions of lncRNAs in acute leukemia have not been well studied. Here, we performed transcriptome‐wide lncRNA expression profiling of acute myeloid leukemia (AML) patient samples, along with non‐leukemia control hematopoietic samples. We found that lncRNAs were differentially expressed in AML samples relative to control samples. Notably, we identified that lncRNAs upregulated in AML (relative to the control samples) are associated with a lower degree of DNA methylation and a higher ratio of being bound by transcription factors such as SP1, STAT4, ATF‐2 and ELK‐1 compared with those downregulated in AML. Moreover, an enrichment of H3K4me3 and a depletion of H3K27me3 were observed in upregulated lncRNAs in AML. Expression patterns of three types of lncRNAs (antisense, enhancer and intergenic lncRNAs) have previously been characterized. Of the identified lncRNAs, we found that high expression level lncRNA LOC285758 is associated with the poor prognosis in AML patients. Furthermore, we found that LOC285758 regulates proliferation of AML cell lines by enhancing the expression of HDAC2, a key factor in carcinogenesis. Collectively, our study depicts a landscape of important lncRNAs in AML and provides novel potential therapeutic targets and prognostic markers for AML treatment.

[1]  S. Emmrich,et al.  LincRNAs MONC and MIR100HG act as oncogenes in acute megakaryoblastic leukemia , 2014, Molecular Cancer.

[2]  Andrew H. Beck,et al.  Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers , 2012, Genome Biology.

[3]  Ji-fan Hu,et al.  An intragenic long noncoding RNA interacts epigenetically with the RUNX1 promoter and enhancer chromatin DNA in hematopoietic malignancies , 2014, International journal of cancer.

[4]  R. Guigó,et al.  Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs , 2014, European heart journal.

[5]  O. Elemento,et al.  A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis , 2013, Nature.

[6]  Yi Zhang,et al.  Role of H3K27 methylation in the regulation of lncRNA expression , 2010, Cell Research.

[7]  Hiromu Suzuki,et al.  A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer , 2016, Scientific Reports.

[8]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[9]  Alessandro Fatica,et al.  Long Non-Coding RNAs: New Players in Hematopoiesis and Leukemia , 2015, Front. Med..

[10]  T. Yamazaki,et al.  Long noncoding RNA, CCDC26, controls myeloid leukemia cell growth through regulation of KIT expression , 2015, Molecular Cancer.

[11]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[12]  Kecheng Zhang,et al.  Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2 , 2010, Cell Death and Disease.

[13]  T. Ørntoft,et al.  Identification of expressed and conserved human noncoding RNAs , 2014, RNA.

[14]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[15]  Fidel Ramírez,et al.  deepTools: a flexible platform for exploring deep-sequencing data , 2014, Nucleic Acids Res..

[16]  G. Dranitsaris,et al.  CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. , 2010, Leukemia research.

[17]  J. Kleinman,et al.  Increased expression of MARCKS in post-mortem brain of violent suicide completers is related to transcription of a long, noncoding, antisense RNA , 2014, Molecular Psychiatry.

[18]  Howard Y. Chang,et al.  Systematic Characterization of Long Noncoding RNAs Reveals the Contrasting Coordination of Cis- and Trans-Molecular Regulation in Human Fetal and Adult Hearts , 2016, Circulation. Cardiovascular genetics.

[19]  Felix Krueger,et al.  Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications , 2011, Bioinform..

[20]  Łukasz M. Boryń,et al.  Transcriptional plasticity promotes primary and acquired resistance to BET inhibition , 2015, Nature.

[21]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[22]  Vincent L. Butty,et al.  Braveheart, a Long Noncoding RNA Required for Cardiovascular Lineage Commitment , 2013, Cell.

[23]  A. Bhan,et al.  Antisense transcript long noncoding RNA (lncRNA) HOTAIR is transcriptionally induced by estradiol. , 2013, Journal of molecular biology.

[24]  Aaron R. Quinlan,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2022 .

[25]  T. Derrien,et al.  Long Noncoding RNAs with Enhancer-like Function in Human Cells , 2010, Cell.

[26]  L. Pennacchio,et al.  Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease , 2014, Journal of molecular and cellular cardiology.

[27]  Ji-zong Zhao,et al.  Differential long non‑coding RNA and mRNA expression in differentiated human glioblastoma stem cells. , 2016, Molecular medicine reports.

[28]  T. Haferlach,et al.  Diagnostic pathways in acute leukemias: a proposal for a multimodal approach , 2007, Annals of Hematology.

[29]  S. Weissman,et al.  Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells , 2014, RNA biology.

[30]  Monika S. Kowalczyk,et al.  Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs , 2013, Genome Biology.

[31]  A. Hoffman,et al.  A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies , 2014, Nucleic acids research.

[32]  Bo W. Han,et al.  A distinct set of long non-coding RNAs in childhood MLL-rearranged acute lymphoblastic leukemia: biology and epigenetic target. , 2014, Human molecular genetics.

[33]  Guido Marcucci,et al.  Expression and prognostic impact of lncRNAs in acute myeloid leukemia , 2014, Proceedings of the National Academy of Sciences.

[34]  M. Caligiuri,et al.  Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML. , 2012, Blood.