Table 1.
ncRNAs associated to Hallmarks of Cancer in CLL.
| Non Coding RNA | Mechanism | Levels IN CLL | Ref | |
|---|---|---|---|---|
| Angiogenesis | miR-92-1 | Represses pVHL and stabilizes HIF-1α, activating VEGF expression | overexpressed | [67] |
| miR-155-5p | Targets HIF-1α | High in aggressive disease | [68] | |
| miR-30d | Inhibits MYPT1, increases phosphorylation levels of c-JUN and activates VEGFA signaling cascade | Reduction | [69] | |
| miR-17/92 cluster | Targets SMAD4 and inhibits TGF-β responses | overexpression | [71,72] | |
| Enabling Replicative Immortality | TERRA/TERC | Inhibition of TERT | Overexpressed in CLL | [60,61,62] |
| Genomic Instability | AC012065.7 | positive expression correlation with GDF7 | Promoter hypo-methylated | [80] |
| CRNDE | Interacts with PRC2 and CoREST to modulate transcriptional repression | Promoter hyper -methylation | [80] | |
| BM742401 | Its expression leads to inhibition of cellular proliferation and enhanced apoptosis through caspase-9-dependent intrinsic but not caspase-8-dependent extrinsic apoptosis pathways | Methylated in CLL | [52] | |
| treRNA | decreases DNA damage and sensitivity to chemotherapy, | highly expressed, correlates with shorter overall survival (OS) | [53] | |
| BGL3 | regulates the oncogenic expression of BCR-ABL fusion gene through c-Myc mediated signaling | Decrease in CLL | [54] | |
| miR-34a | Downregulation of FOXP1, limiting BCR signaling | Upregulated during DNA damage response | [58] | |
| Resisting Cell Death | miR-15a, miR-16-1 | Target and deregulate BCL2 | Deleted in 13q- CLL | [24,25] |
| lincRNA-p21 | Induced by p53Induces p21 through hnRNP-K binding | Increased in p53WT samples | [32,33,34] | |
| HULC | endogenous sponge downregulating miRNAs, including miR-372 and miR-200a-3p | Upregulated in CLL | [42] | |
| MIAT | Constitution of a regulatory loop with OCT4 | Increased in patients with poor OS | [19,20] | |
| Circ_0132266 | endogenous sponge of hsa-miR-337-3p resulting in a downstream change of target-gene promyelocytic leukemia protein (PML) | decreased in the PBMCs of CLL patients | [48] | |
| Sustaining Proliferative Signaling | miR-17/92 cluster | mechanism is poorly understood, but up-regulation of miRNAs belonging to the miR-17-92 cluster is preceded by induction of MYC | Overexpressed in CLL | [11,12,13,14] |
| miR-29, miR-181 | Targeting TCL1 | Downregulated in CLL | [40] | |
| miR-155 | transcriptionally activated by MYB, leads to downregulation of several tumor suppressor genes. | Increased in CLL | [45] | |
| DLEU1, DLEU2 | NF-kB activation. Host of miR-15a/16-1 cluster targeting BCL2 | Homozygosis loss | [26,27,29] | |
| lnc-TOMM7-1 | It maps to chromosome 7p antisense to the interleukin-6 (IL6) gene and participate to its transcriptional regulation | downregulation | [46] | |
| circ_CBFB | acts as a sponge for miR-607, and contributes to the regulation of the Wnt/β-catenin pathway | highly upregulated | [47] | |
| ts-53, ts-101 | tsRNAs that play regulatory roles associating with Argonaute proteins | down-regulated in all CLL types | [40] | |
| Tumor Microenvironment | miR-21 | Transcriptionally activated by ZAP70, enhancer of BCR signaling | overexpression | [77,78,79] |
| miR-155-5p | Decreases SHIP1, resulting in higher responsiveness to BCR ligatio | upregulated | [81] | |
| miR-181a/miR-181b | regulated by TGF-β, they target BCL− 2, MCL-1 and XIAP | Downregulated | [84,85] | |
| miR-125-b | negatively regulates MS4A1 | levels in circulation are inversely correlated with rituximab-induced lymphodepletion | [87,88] | |
| miR-19b | Upregulates Ki67 and downregulates TP53 | Upregulated in plasma-derived exosomes in CLL | [100] | |
| miR-202-3p | It targets Sufu, a negative regulator of Hedgehog signaling | selectively enriched in CLL-derived EVs | [102] | |
| Linc-Cox2 | Acts as scaffold molecule recruiting SWI/SNF complex, activating the late primary inflammatory NF-κB-dependent genes | highly induced in macrophages upon TLR ligation | [93] | |
| LINC00461 | Directly correlates with decrease ERK1/2 and AKT activities and expression levels of miR-9, MEF2C and TMEM161B | highly expressed in MSCs-derived exosomes | [101] | |
| PACER | regulates COX-2 expression and acts as a decoy lncRNA for NF-kB signaling | n.d. | [92] |
Abbreviations: pVHL: von-Hippel Lindau tumor suppressor, HIF-1α: Hypoxia-inducible factor 1-alpha, VEGF: Vascular Endothelial Growth Factor, MYPT1: Myosin Phosphatase Target Subunit 1, TGF-β: transforming growth factor beta, TERT: telomerase reverse transcriptase, GDF7: growth differentiation factor 7, PRC2: polycomb repressive complex 2, CoREST: REST corepressor, FOXP1: Forkhead box protein P1, BCR: B cell receptor, BCL2: B-cell lymphoma 2, hnRNP-k: Heterogeneous nuclear ribonucleoprotein K, MCL-1: Induced myeloid leukemia cell differentiation, Cox-2: Cyclooxygenase-2.