Identification of novel lncRNAs involved in the pathogenesis of childhood acute lymphoblastic leukemia
- Authors:
- Published online on: December 14, 2018 https://doi.org/10.3892/ol.2018.9832
- Pages: 2081-2090
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Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Childhood acute lymphoblastic leukemia (cALL) arises more often from B-cell lineages than from T-cell lineages (1). The survival rate of cALL is significantly superior in children compared with in adolescents and adults, partly due to the higher prevalence of favorable genetic variations in children, including myeloid/lymphoid leukemia (MLL), cytokine receptor-like factor 2, ETS variant gene 6-runt-related transcription factor 1 and hyperdiploidy (2). After 40 years of research, the cure rate for cALL has significantly improved, and the overall 5-year event-free survival rate has reached ~90% (3). Despite this progress, 10–20% of patients experience relapses, and their prognoses are poor, even after receiving allogeneic stem cell transplantation (4,5). Therefore, it is crucial to further explore the pathogenesis of cALL, particularly its recurrence, and to develop novel treatment strategies. Long non-coding RNAs (lncRNAs) belong to a class of transcripts with no protein-coding capacity, which are >200 bp long (6). Previous studies have demonstrated that lncRNAs have a wide range of regulatory effects on tumorigenesis, including proliferation (7), migration (8), invasion (9), apoptosis (10) and recurrence (11). In addition, mechanisms underlying the involvement of lncRNAs in cALL have previously been explored. Fang et al reported that a set of lncRNAs affects proliferation and apoptosis in MLL-rearranged-cALL via co-expression with the homeobox A gene cluster (12). Trimarchi et al also demonstrated that the lncRNA LUNAR1 is essential for the growth of T-cell ALL (T-ALL) and maintains high expression levels of insulin-like growth factor 1 receptor via a cis-activation mechanism (13). In addition, Trimarchi et al documented that several lncRNAs can be regulated by Notch activity in T-ALL (13). Wang et al demonstrated that the lncRNA NALT interacts with Notch homolog 1, translocation-associated to promote cell proliferation in T-ALL (14). These findings indicated that lncRNAs may serve essential roles in ALL, including cALL.
In 2016, Yeoh et al (15) previously constructed an RNA-seq dataset of the time-dependent gene expression profiles of patients with cALL (GSE67684; http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE67684) and revealed that effective response metric was a prognostic factor. This dataset was then analyzed by another research group, which revealed that microRNA-590 promotes cell proliferation and invasion in T-ALL via suppression of RB transcriptional corepressor 1 (16). To further explore the mechanism underlying the involvement of lncRNAs in cALL, this RNA-seq dataset was re-analyzed in the current study using bioinformatics methods to provide novel insights into the ontogeny and treatment of cALL.
Materials and methods
Data source
A time-series gene expression profiling dataset, GSE67684, was downloaded from the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE67684). A total of 495 cALL blood samples from 210 children (111 males, 90 females and 9 unknown with 160 patients between 1–10 years and 50 patients <1 or >10 years) were used in this study, including 194 at Day 0, 193 at Day 8, 49 at Day 15 and 59 at Day 33 post-diagnosis. In this time series dataset, expression levels of lncRNAs and mRNAs were detected using the GPL570 [HG-U133 Plus 2] Affymetrix Human Genome U133 Plus 2.0 Array and GPL96 [HG-U133A] Affymetrix Human Genome U133A Array, respectively platforms, respectively (Affymetrix; Thermo Fisher Scientific, Inc., Waltham, MA, USA).
Identification of differentially expressed genes (DEGs) and lncRNAs (DELs)
According to the annotation profiles provided by the GPL570 [HG-U133 Plus 2] Affymetrix Human Genome U133 Plus 2.0 Array, expression information of lncRNA-associated probes was analyzed using ExpressionConsole (version 1.1; Affymetrix; Thermo Fisher Scientific, Inc.) to evaluate the gene expression levels. BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) was used to annotate the probes matched to lncRNAs. Additionally, expression information of mRNA-associated probes was analyzed using ExpressionConsole based on the information provided by GPL96 [HG-U133A] Affymetrix Human Genome U133A Array. Subsequently, DEGs and DELs between Day 0, 8, 15 and 33 were screened using random variance model corrective analysis of variance in R 3.5.1 software (https://cran.r-project.org/). Thresholds of DEGs and DELs were set as follows: P≤0.001, false discovery rate (FDR) ≤0.01, and fold change ≥2. Numbers of screened DEGs and DELs were illustrated using Venn diagrams.
Clustering analysis of overlapping DEGs and DELs
Using Venn diagrams, overlapping DEGs and DELs were clustered using Cluster 3.0 (http://bonsai.hgc.jp/~mdehoon/software/cluster/software.htm). Based on these results, significantly different DEG and DEL profiles (clusters) over time were selected using a series test of cluster approach, as previously described (17,18), with P<0.05.
Enrichment analysis of DEGs
To explore the biological functions of DEGs and the pathways in which they are involved, function and pathway enrichments of DEG profiles were conducted using the Database for Annotation, Visualization and Integration Discovery (DAVID; http://david.abcc.ncifcrf.gov/) based on the Gene Ontology (GO; http://www.geneontology.org/) and the Kyoto Encyclopedia of Genes and Genomes (KEGG; http://www.genome.jp/kegg/pathway.html) databases. GO terms and KEGG pathways were considered significantly enriched when the following criteria were met: P≤0.05 and FDR <0.05.
Construction of the lncRNA-mRNA network
According to the significantly enriched GO terms and KEGG pathways, overlapping mRNAs were selected. Using the overlapping mRNA (obtained based on the enrichment of GO terms and KEGG pathways) and overlapping lncRNAs, the interactions between lncRNAs and mRNAs were evaluated using dynamic simulations based on gene-sample matrices, and the Pearson correlation coefficient of each lncRNA-mRNA pair was calculated using the function cor.test (X, Y, method = ‘Pearson’) of R software (19). The pairs with Pearson correlation coefficients >0.8 and P<0.05 were selected; subsequently, the lncRNA-mRNA network was constructed using Cytoscape version 3.0.2 (http://chianti.ucsd.edu/cytoscape-3.0.2/).
Construction of protein-protein interaction network (PPI)
Based on the lncRNA-mRNA network, co-expressed DEGs involved in this network were selected, and the interactions among them were predicted using the Search Tool for the Retrieval of Interacting Genes (STRING; version 10.0; http://www.string-db.org/) database (functional protein interaction networks). Interactions among proteins were visualized using Cytoscape version 3.0.2 based on these predicted relationship pairs.
Validation of DEL expression
This study was approved by the Clinical Research Ethics Committee of The First Affiliated Hospital of Nanjing Medical University (Nanjing, China). From March 2016 to July 2017, 44 subjects (23 males, 21 females, with mean age of 7.5 years) were recruited including 14 controls and 30 with cALL. Informed consent was obtained from the subjects' parents prior to participation. A total of 14 blood samples (four without cALL and 10 with cALL) were analyzed using RT-qPCR to verify the expression of DELs identified in this study. In addition, 30 bone marrow samples, including 10 controls and 20 with cALL, were collected to confirm the findings using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The samples in the cALL group were collected from patients with recurrent cALL who were receiving methotrexate chemotherapy and the samples in the control group were collected from healthy individuals. Total RNA was isolated using TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, Inc.) and was quantified using a NanoDrop spectrophotometer (NanoDrop; Thermo Fisher Scientific, Inc., Wilmington, DE, USA). Subsequently, 1 µg total RNA was reverse transcribed to cDNA using a SuperScript III transcript kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA), according to the manufacturer's protocol. Amplification was performed using SYBR reagent (Thermo Fisher Scientific, Inc.) on a Thermo 7500 PCR thermocycler (Thermo Fisher Scientific, Inc.) with the following reaction conditions: 95°C for 20 sec, followed by 40 cycles at 95°C for 3 sec and 60°C for 30 sec. GAPDH was used as the internal control for quantitative analysis with the 2−ΔΔCq method (20). Primers of lncRNAs and GAPDH were designed as follows: NONHSAT027612.2, forward, 5′-GAGTGCAGTGGCGTGATCTT-3′ and reverse, 5′-GTGGTGGTGCATGCCTGTAGT-3′; NONHSAT134556.2; forward, 5′-GATCATGCGGTTAAGGAGTGTG-3′ and reverse, 5′-TCATCCTGCTAAGCGCTGAG-3′; GAPDH, forward, 5′-GTGGAGTCCACTGGCGTCTT-3′ and reverse 5′-GTGCAGGAGGCATTGCTGAT-3′. Data are presented as the means ± standard deviation. Comparisons between groups were performed using Student's t-test in SPSS version 15.0 software (SPSS, Inc., Chicago, IL, USA) and P<0.05 was considered to indicate a statistically significant difference.
Results
Identification of DEGs and DELs
According to the selected thresholds, a total of 748, 1,895 and 2,428 DEGs were identified in the comparisons of Day 0 with Day 8, Day 0 with Day 15, and Day 0 with Day 33, respectively (Fig. 1A). Among these, 593 overlapping DEGs were identified. In addition, a total of 39, 162 and 207 DELs were identified when Day 0 results were compared with results from Day 8, 15 and 33, respectively (Fig. 1B). Among these, 21 overlapping DELs were identified.
Cluster analysis of overlapping DEGs and DELs
According to the Venn diagram, the overlapping DEGs were clustered (Fig. 2A) to screen for gene profiles with significant variations. A total of eight significantly different profiles were identified, including five upregulated (Profiles 17, 23, 24, 25 and 26) and three downregulated (Profiles 1, 2 and 10) profiles. DEGs included in each of these profiles exhibited a similar tendency to change compared with other DEGs. Furthermore, overlapping DELs were similarly clustered (Fig. 2B) to select those that showed significant variation, and a total of eight profiles were identified, including four upregulated profiles (Profiles 23, 24, 25 and 26) and four downregulated profiles (Profiles 1, 2, 3 and 10). In addition, DELs included in each profile exhibited a similar tendency to change compared with other DELs. Among these profiles, Profile 26 exhibited a continuous increase over time, whereas Profile 1 exhibited a continuous decrease.
Enrichment analyses of DEGs
Upregulated DEG profiles were significantly enriched in 1,825 GO terms, such as small molecule metabolic process (P=4.64×10−67), signal transduction (P=7.44×10−65), innate immune response (P=1.95×10−63), blood coagulation (P=3.41×10−62) and immune response (P=9.61×10−59). Downregulated DEG profiles were enriched in 196 GO terms, such as transcription DNA-dependent (P=2.32×10−49), regulation of transcription, DNA-dependent (P=1.36×10−43), negative regulation of transcription from RNA polymerase II promoter (P=3.65×10−25), positive regulation of transcription from RNA polymerase II promoter (P=2.48×10−22) and positive regulation of transcription, DNA-dependent (P=1.54×10−19; Table I).
KEGG enrichment analysis revealed that upregulated DEG profiles were significantly enriched in 166 KEGG pathways, including metabolic pathways (P=1.10×10−43), cytokine-cytokine receptor interaction (P=5.71×10−31), osteoclast differentiation (P=4.96×10−30), phagosome (P=1.69×10−29) and lysosome (P=1.72×10−27). Downregulated DEGs were significantly enriched in 90 KEGG terms, such as pathways in cancer (P=2.33×10−12), systemic lupus erythematous (P=8.32×10−12), cell adhesion molecules (CAMs) (P=2.29×10−10), aldosterone synthesis and secretion (P=2.34×10−9) and HTLV-1 infection (P=5.94×10−9; Table II). Profile 26, which exhibited continuous increase, was significantly enriched in the following GO terms: Signal transduction (P=9.64×10−25), small molecule metabolic process (P=2.58×10−22), blood coagulation (P=2.73×10-21), etc.; and the following KEGG pathways: Metabolic pathways (P=3.33×10−18), lysosome (P=6.37×10−17), TNF signaling pathway (P=3.27×10−11), etc. (Table III). The continuously decreasing Profile 1 was significantly enriched in the following GO terms: Transcription DNA-dependent (P=1.74×10−28), regulation of transcription, DNA-dependent (P=8.48×10−20), negative regulation of transcription from RNA polymerase II promoter (P=1.34×10−17), etc.; and the following KEGG pathways: cGMP-PKG signaling pathway (P=1.88×10−7), Rap1 signaling pathway (P=1.65×10−6), glutamatergic synapse (P=1.69×10−5), etc. (Table III).
LncRNA-mRNA network
A lncRNA-mRNA network of overlapping lncRNAs and mRNAs was constructed based on the calculation of dynamic simulations (Fig. 3). This network comprised 26 lncRNAs and 103 mRNAs with 179 interaction pairs. NONHSAT134556.2 was the lncRNA with the highest regulatory capability (degree=58), followed by NONHSAT027612.2 (degree=54). The top five target DEGs of lncRNAs were pleckstrin and Sec7 domain containing 3 (degree=4), serpin family B member 10 (degree=4), STEAP3 metalloreductase (degree=3), succinate receptor 1 (degree=3) and microsomal glutathione S-transferase 1 (degree=3).
PPI network
Based on the lncRNA-mRNA network, mRNAs were selected to construct a PPI network using the STRING database (Fig. 4). This network comprised 80 mRNA-coded proteins and 147 interaction pairs. The top 10 hub nodes of this network were Toll-like receptor 4 (TLR4) (degree=15), integrin subunit αM (degree=14), cathepsin G (CTSG) (degree=13), lysozyme (degree=11), matrix metallopeptidase 9 (MMP9) (degree=11), nucleotide-binding oligomerization domain-containing 2 (NOD2) (degree=10), cathepsin S (CTSS) (degree=8), formyl peptide receptor 1 (FPR1) (degree=8), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (degree=8) and serpin family A member 1 (degree=8).
Validation of DELs
To confirm the present findings, variations in the expression levels of NONHSAT027612.2 and NONHSAT134556.2 were verified in the blood and bone marrow of patients with cALL. The results revealed that the expression levels of NONHSAT027612.2 and NONHSAT134556.2 were significantly increased in blood and bone marrow samples of patients with cALL compared with in the control samples (Fig. 5). These verifications were consistent with the results obtained from bioinformatics analysis.
Discussion
In the current study, the gene dataset GSE67684 was re-analyzed, and 593 DEGs and 21 DELs were identified that varied over time post-diagnosis of cALL. Among the clustered DEGs, Profile 26 presented a tendency to increase across all time points, whereas Profile 1 tended to decrease over the same interval. GO enrichment analysis revealed that Profiles 26 and 1 were significantly enriched in immune response (GO:0006955, immune response; GO:0045087, innate immune response) and proliferation-associated biological (GO:0050680, negative regulation of epithelial cell proliferation) processes, respectively. In addition, the lncRNAs NONHSAT027612.2 and NONHSAT134556.2 were revealed to be significantly upregulated in cALL and could regulate most upregulated DEGs identified in this study.
Previous studies have reported that lncRNAs exhibit a wide array of regulatory effects on gene expression (21,22). The lncRNAs NONHSAT027612.2 and NONHSAT134556.2, which are newly identified lncRNAs, are located on chromosomes 12 and 9, respectively. At present, to the best of our knowledge, only sequencing of their expression levels in tissues has been reported (http://www.noncode.org/). In the present study, the lncRNAs NONHSAT027612.2 and NONHSAT134556.2 were significantly elevated in cALL samples compared with in control blood and bone marrow samples. Further analysis demonstrated that NONHSAT027612.2 directly upregulated the expression levels of TLR4 and its regulator, NOD2. In addition, NONHSAT134556.2 directly upregulated the expression of TLR4. TLR4 and NOD2 are key genes involved in innate immunity (23); they were both identified in this study and are expected to interact with each other. Previous studies have demonstrated that TLR4 promotes B-cell maturation (24), and that TLR4 polymorphisms are associated with neutropenia development in cALL (25). He et al also reported that TLR4 signaling promotes immune-escape evasion in human pulmonary cancer cells by inducing apoptosis resistance and immunosuppressive cytokine expression (26). Furthermore, TLR4 stimulation induces delayed activation of the nuclear factor-κB subunit Rel A (27), which is reported to serve a crucial role in in vitro survival and clinical progression of chronic lymphocytic leukemia (28). Chronic lymphocytic leukemia cells are unresponsive to TLR4 and TLR8 stimulation (29), which may explain the upregulation of TLR4 and TLR8 in cALL observed in the present study. Whether a feedback mechanism exists between TLR4 and the response of chronic lymphocytic leukemia cells requires further investigation. As important regulators of TLRs, NOD2 polymorphisms are also associated with increased relapse and mortality rates in patients with ALL who have undergone hematopoietic stem-cell transplantation (30). NOD2 is an intracellular protein that recognizes bacterial peptidoglycans. This protein is widely expressed in cells, including B cells, in which interaction among TLRs occurs (31). In the current study, NOD2 was revealed to interact with TLR4 and TLR8, and its expression was significantly enriched in the innate immune response and TLR signaling pathways. Muzio et al demonstrated that NOD2 and other TLR ligands, particularly TLR1/2 and TLR6/2, induce the activation of chronic lymphocytic leukemia cells via induction of IκB kinase phosphorylation and elevation of the expression of cluster of differentiation (CD) 25 and CD86 (32). Furthermore, NOD2 is functionally relevant in regulatory T cells and inhibits Fas-mediated apoptosis in T cells (33). However, a deeper understanding of the signal transduction and interaction between TLR4 and NOD2 in cALL remains to be established.
CTSG and CTSS are genes coding for the proteins cathepsin G and cathepsin S, which belong to the cathepsin family (34), and are involved in the immune response. CTSG and CTSS were revealed to be upregulated by lncRNAs NONHSAT134556.2 and NONHSAT027612.2, respectively. Chang et al reported that the expression of CTSG is significantly downregulated, alongside interleukin-6 (IL-6), IL-8, IL-12 and B-cell lymphoma 2 in HT1080 cells via tilapia hepcidin 1–5, which is an antimicrobial peptide that possesses potential anticancer activity (35). Zöller (36) suggested out that CTSG and MMP9-activated transforming growth factor-β contribute to bone resorption and niche preparation for cancer-initiating cells. Other studies have suggested that CTSG is activated by various classes of proteinases, such as MMPs or serine/cysteine proteinases, during the development of human disease (37). These observations indicated that CTSG serves a positive role in carcinogenesis. In agreement with the present observations, CTSS expression is elevated in pancreatic cancer and results in the production of γ2 peptide, which is an important molecule involved in cell adhesion, migration and metastasis during carcinogenesis (38,39). CTSS is also involved in protumorigenic activities during intestinal carcinogenesis (40). Other studies have documented that CTSS has an important role in the migration and invasion of gastric cancer cells via a network of metastasis-associated proteins (41). Taken together, these findings indicated that CTSG and CTSS may have important roles in tumorigenesis and could serve as potential targets for tumor treatment. However, the underlying mechanisms of CTSG and CTSS in cALL remain unknown and warrant further analysis.
Although this study revealed some interesting results, it also presented some limitations. Firstly, the majority of results were identified in silico; therefore, further experimental validation is required. Secondly, the parameters used were set manually; therefore, some genes may have been ignored due to thresholds. Thirdly, although the study validated the findings, the expression levels of NONHSAT134556.2 and NONHSAT134556.2 were not consistent with their degree in the regulatory network; therefore, a larger sample size will be required in further studies. Finally, due to limited resources, not enough cALL samples at Day 0 were collected; therefore blood samples from healthy subjects were collected instead and used as controls in the present study, which could induce a bias. Considering these limitations, we aim to further confirm these findings using cALL samples collected from patients at Day 0 as controls as soon as enough samples are collected.
In conclusion, the expression levels of the lncRNAs NONHSAT027612.2 and NONHSAT134556.2 were significantly increased in patients with cALL, and may serve as potential regulators for the pathogenesis of cALL. From these two lncRNAs, TLR4, NOD2, CTSG and CTSS may be potential gene targets, and may promote development of cALL via immune response-associated biological processes.
Acknowledgements
Not applicable.
Funding
This study was supported by the National Natural Science Foundation of China (grant nos. 30872804, 81170661 and 31640048 to GPZ) and Jiangsu Province Science and Education Enhancing Health Project Innovation Team (Leading Talent) Program (no. CXTDA2017018 to GPZ).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
GZ and YF conceived and designed the study. SL and HB performed the data analysis and wrote the manuscript. YC identified the DEGs and DELs. CJ performed the GO analysis, KEGG pathway analysis and PPI analysis. QC performed the RT-qPCR. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The Clinical Research Ethics Committee of the First Hospital of Nanjing Medical University approved this study. Informed consent was obtained from the subjects' parents.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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