The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia
Abstract
:Simple Summary
Abstract
1. Introduction
2. cis-Acting RNA Regulatory Motifs
2.1. Aberrant Pre-mRNA Splicing
2.2. Alterations in Untranslated Regions (UTR) of mRNA
2.2.1. 5′ UTR Alterations in Leukemogenesis
2.2.2. 3′ UTR Alterations in Leukemogenesis
3. Prospective Therapeutic Value of Targeting Non-Coding Pre-mRNA and mRNA Sequences
4. Regulatory Non-Coding RNA Molecules
4.1. Long Non-Coding RNA
4.2. Circular RNA
4.3. Short Non-Coding RNAs
miRNA
5. Therapeutic Approaches for Targeting RNA Molecules
6. Concluding Remarks
Funding
Acknowledgments
Conflicts of Interest
References
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lncRNA Gene Name | Type of Cancer | Expression in Cancer | Mechanisms | Gene Expression Regulators | Ref |
---|---|---|---|---|---|
Nuclear Function: Chromatin Folding and Transcription | |||||
HOTTIP | MLLr+ NPM1C+ AML | Upregulated | Remodels chromatin accessibility and alters hematopoietic transcription programs affecting multiple pathways (cell cycle, apoptosis, myeloid/leukocyte cell differentiation, JAK-STAT signaling, and regulation of cell development); promotes HSCs self-renewal leading to AML-like disease in mice; lower survival in AML patients | CCCTC-binding factor (CTCF) active at a binding site located between HOXA7 and HOXA9 genes (CBS7/9); Psip1/p52 | [91,94,101] |
MAGI2-AS3 | AML | Downregulated | Inhibits self-renewal in leukemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukemia; a better survival with overexpression | Unknown | [98] |
IRAIN | AML | Downregulated | Intrachromosomal interactions, enhancer-promoter loop within IGF1R gene | Unknown | [100] |
MALAT1 | AML, CLL, CMML, MM, HCC, other cancers | Upregulated | Regulates the phosphorylation status of serin-rich splicing factors (SRSF), their subcellular localization in HeLa cells; interacts with PCR2, transcription factors and sequesters miRNA in the cytoplasm. Aberrant expression in Del 13q14 CLL; MALAT1 depletion increases cytarabine sensitivity in AML and response to ATRA-treatment in CMML | Multiple transcription factors e.g., SP1, SP3, HIF1-alpha, c-MYC | Reviewed in [93] |
CASC15 | RUNX1r+ B-ALL, AML | Upregulated | CASC15 regulates expression of SOX4 (B cell reg.) and YY1; overexpression opposes cellular proliferation and promotes myeloid bias in vivo; associated with a better prognosis | HIF1-alpha hypoxia sensitive elements within CASC15 promoter | [96,97] |
ARIEL | TAL1+ T-ALL | Upregulated | Enhancer RNA: recruits mediator proteins to the ARID5B enhancer, promotes enhancer-promoter interactions, activates ARID5B expression, thereby positively regulating the TAL1-induced transcriptional program and MYC oncogene | ARIEL transcription is activated by TAL1 complex | [92] |
LUNAR1 | NOTCH-regulated T-ALL | Downregulated | enhancer lncRNA: activates IGF1R expression, T cell proliferation | Regulated by NOTCH1 | [88,90] |
Cytoplasmic Function: Protein Translation, mRNA Stability | |||||
AS-RBM15 | AMKL | Downregulated | AS-RBM15 promotes terminal differentiation by enhancing RBM15 translation in a 5′ cap-dependent manner. The overlapping region between AS-RBM15 RNA and 5′ UTR of RBM15 mRNA function as enhancer of RBM15 protein synthesis | AS-RBM15 transcription is activated by RUNX1 and repressed by RUNX1-ETO | [95] |
PU.1-AS | AML | Upregulated | The simultaneous expression of both sense mRNA and anti-sense RNA (PU.1-AS) transcripts; PU.1-AS RNAs consist ~12–15% of PU.1 mRNA level but are more stable than PU.1 mRNA; PU.1-AS RNA forms complex with eIF4A and stalls PU.1 mRNA translation between initiation and elongation steps | Upstream regulatory element (URE) which physically interacts with both sense and anti-sense promoters; CBF fusions (RUNX1-ETO and CBFβ-MYH11) in AML | [102,103] |
UCA1 | AML, breast cancer, other types | Upregulated | hnRNP1 is a splicing factor that also promotes cap-independent translation through binding with IRES and recruiting ribosomes to p53 and p27 (Kip1) mRNAs. lncRNA UCA1 binding with phosphorylated cytosolic form of hnRNP1 has anti-apoptotic effect in breast cancer. In leukemia, UCA1 sponges for miR-126, miR-125a, miR-16, and activates PI3K/AKT and JAK/STAT signaling | Regulated by CCAAT/enhancer-binding protein-alpha | [89,99,104,105] |
lncRNA Gene Name | Type of Cancer | Study Design | Expression in Cancer | Prognostic Significance or Function in Cancer | Ref |
---|---|---|---|---|---|
SNHG1 | AML pediatric | newly diagnosed AML (n = 209), healthy controls(n = 67), BM, qRT-PCR | upregulated | shorter event-free and overall survival (p < 0.001) | [128] |
SOX6-1 | AML pediatric | de novo AML (n = 146), nonhematologic cancer controls(n = 73), BM, proliferation, qRT-PCR apoptosis CCK-8 and AV/PI assay | upregulated | poor-risk stratification, overall survival (p < 0.001), | [129] |
LINC00909 | AML pediatric | untreated AML (n = 93), healthy controls (n = 31), BM, RT-qPCR analysis, RNA-pull down; luciferase reporter assay; cell viability, migration | upregulated | sponge miR-625, activate WNT-signaling, poor prognosis, AML progression | [124] |
UCA1 | AML pediatric | UCA1 expression in AML (n = 27) before and after adriamycin (ADR)-based chemotherapy, cell lines, qRT-PCR, luciferase reporter assay, RIP | upregulated | chemoresistance, inhibits glycolysis through the microRNA-125a/hexokinase 2 pathway | [105] |
UCA1 | AML pediatric | untreated AML (n = 27), PB healthy donor controls, cell lines | upregulated | sustains AML proliferation similar to adult AML | [125] |
H19 | AML pediatric | gene expression profiles from 1361 childhood leukemia patients in 14 independent studies using available Affymetrix data | upregulated | LIN28B and LIN28B-driven H19 expression present in aggressive subsets of pediatric leukemia | [120] |
ENST00000435695 ENST00000415964 | AML pediatric | Arraystar Human IncRNA Array V3.0 in three AML vs. controls followed by qRT-PCR in AML BM (n = 22) | 372 dysregulated IncRNAs (difference ≥ 10-fold) | ENST00000435695 (most upregulated) ENST00000415964 (most downregulated) | [133] |
lnc-THADA4-1 lnc-SUPT3H-1 | JMML pediatric | lncRNA landscapes in untreated JMML (n = 44, n = 19) and healthy BM donors, clinical and molecular characteristics, lncRNA-mRNA interaction network, LNA™ GapmeRs inhibition, cell viability | lnc-THADA4-1 (highest) lnc-SUPT3H-1 (lowest) lncRNA specific for granulocytic lineage– lnc-ACSL1-1,lnc-BASP1-3 | Defined lncRNA associated with favorable and unfavorable prognosis, JMML lncRNA score: difference in the event-free survival from HSCT is significant, p < 0.0001 | [131,132] |
TCL6 CCDC26 | B-ALL pediatric | ETV6-RUNX1-positive (n = 24) versus ETV6-RUNX1-negative (n = 18) B-ALL, RNA seq, clustering analysis | TCL6(highest) CCDC26(lowest) | TCL6 levels may be associated with poor disease-free survival, even within ETV6-RUNX1-positive B-ALL (p < 0.05) | [130] |
CDKN2B-AS (ANRIL) | B-ALL pediatric | genotype association study 217 B-ALL patients and 338 controls in CDKN2A/B (9p21.3) locus containing lnc-ANRIL | SNP | Six SNP inducing most strongly associated with B-ALL susceptibility rs2811712 located in the intron 1 on lnc-ANRIL | [21] |
BALR-2, (BALR-6, LIN00958) | B-ALL pediatric | pediatric B-ALL MLLr+, TEL-AML1, E2A-PBX1, BCR-ABL1 (n = 160) | Upregulated | Poor overall survival (p = 0.005) | [134] |
AWPPH | T-ALL pediatric | de novo, untreated T-ALL (n = 32) healthy controls, BM, cell proliferation, apoptosis | upregulated | supports proliferation and inhibits apoptosis | [126] |
CDKN2B-AS1 | T-ALL pediatric | de novo untreated T-ALL (n = 21) and ADR-based therapies treated (n = 21), total T-ALL patients (n = 42), IP, RIP, Luc assay; | upregulated | ADR resistance, positive regulation of TRAF5 through miR-335-3p sponging | [127] |
INSR | T-ALL pediatric | de novo, untreated T-ALL (n = 3) and healthy BM controls, anti-CD3 sorting, MNC RNAseq, lncRNA cellular localization | upregulated | lnc-INSR promotes tumor progression by promoting an immunosuppressive microenvironment in vivo | [122] |
NALT | T-ALL pediatric | T-ALL (n = 20), BM, proliferation assay in vitro and in vivo PDX | upregulated | Co-expressed and supports NOTCH1 signaling, nuclear localization, novel cis-acting element regulating NOTCH1 | [121] |
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Elcheva, I.A.; Spiegelman, V.S. The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia. Cancers 2020, 12, 3854. https://doi.org/10.3390/cancers12123854
Elcheva IA, Spiegelman VS. The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia. Cancers. 2020; 12(12):3854. https://doi.org/10.3390/cancers12123854
Chicago/Turabian StyleElcheva, Irina A., and Vladimir S. Spiegelman. 2020. "The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia" Cancers 12, no. 12: 3854. https://doi.org/10.3390/cancers12123854
APA StyleElcheva, I. A., & Spiegelman, V. S. (2020). The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia. Cancers, 12(12), 3854. https://doi.org/10.3390/cancers12123854