Table 1.
miRNAs involved in ALL immune response.
| T Cells | NK | T Reg | MDSC | T-ALL | Reference | |
|---|---|---|---|---|---|---|
| miR-15-16 | - | Promotes the transition to stage 4 (CD27¯CD11b+) during NK maturation | - | - | Blocks NK cell maturation and leads to accumulation of immature stage-2 and stage-3 cells |
[6] |
| miR-16-2-3p | - | - | Blocks the function in the tumour microenvironment by inhibiting PD1/PDL1 signalling pathway | Blocks the function in the tumour microenvironment by inhibiting PD1/PDL1 signalling pathway | Down-regulation in ALL leads to the recruitment of both MDSCs and Tregs; inhibits functional T-cell responses in ALL |
[7,8] |
| Cluster 17-92 | Increases T-cells proliferation and survival in DN–DP transition; high expression leads to autoimmunity |
- | - | - | Negatively regulates E2F1 to suppress T-ALL apoptosis | [9,10,11] |
| miR-21 | - | - | Induces IL-10 and impairs Treg cell function | - | Up-regulation in T-ALL promotes survival suppressing Pdcd4 at least by stabilization of BCL-XL protein levels; immunosuppressive effects of IL-10 by Tregs leads to unchecked inflammation and promotes T-ALL progression |
[12,13,14] |
| miR-26 | - | - | Promotes Tregs production and function by targeting IL-6 |
- | Down-regulation in T-ALL patients leads to decreased apoptosis and induction of proliferation caused by failed repression of PIK3CD | [15,16] |
| miR-29a/b | miR-29a acts as tumour suppressor targeting DNMT3a and DNMT3b to reduce methylation in leukemic T-cells |
miR-29b represses NK cells cytotoxic function and differentiation in Notch1-T-ALL | - | - | miR-29b downregulation in T-ALL causes altered epigenetic status activating methylation of DNMT3a, DNMT3b and TET1; miR-29b up-regulation via vesicular release by leukemic cells influences NK cell development; miR-29a low expression in T-ALL |
[17,18,19,20] |
| miR-34a-5p | miR-34a acts as tumour suppressor, central NF-κB regulator in T-cell | - | - | Up-regulation of miR- 34a- 5p promotes the expansion of MDSCs | Down-regulation in T-ALL impacts the NF-κB signalosome increasing surface abundance of TCRA and CD3E caused by lost targeting of NF-κBIA and five PKC isozymes | [21,22,23] |
| miR-133b | - | - | Modulates Tregs differentiation by IL-17A expression | - | Reduced expression in association with low levels of IL-17 levels in T-ALL | [16,24] |
| miR-142-3p | Modulated in thymocytes differentiation | - | - | - | Over-expression in T-ALL reduces cAMP levels and interacts with PKA, to increase leukemic T-cell growth; targeting GRa it induces glucorticoid resistance |
[25] |
| miR-146b-5p | High expression in thymocytes regulates the DP–SP transition | - | - | - | Tumour suppressor function delaying progression of T-ALL; Downregulated by over-expressed TAL1 in T-ALL patients | [26] |
| miR-150 | Modulates T-cell differentiation; regulates Notch3 expression |
Promotes NK cell survival and maturation | Up-regulation blocks mTOR pathway and enhances Treg cell differentiation | - | Induces accumulation of hyperfunctional mature NK cells; inversely correlated to Notch3 expression |
[27,28,29] |
| miR-155 | Positively regulates Th17 differentiation. Pivotal role in regulation of T-cell response during T-cell activation | Promotes the transition to stage 4 (CD27¯CD11b+) during NK cell maturation | Targets FOXP3, to modulating Tregs differentiation and function; affects IL-2 production by inhibiting SOCS1 to regulate Treg proliferation | Down-regulation promotes expansion of functional MDSCs by targeting SHIP-1 and PTEN | Blocks NK cell maturation and leads to immature stage 2 and 3 cells accumulation; Low-expression, induced by IL-10, promotes T-ALL progression |
[12,30,31,32,33,34,35,36] |
| miR-181 | High expression during the DP stage and low mature T-cells | Up-regulates Notch signalling in NK cell development by targeting NLK | - | - | Is a tumour suppressor in ALL with over-expression of Smad7 and regulates TGFβ1/Smad pathway | [37,38,39] |
| miR-210 | - | - | Up-regulates FOXP3 and arginase 1, and enhances Treg cells function | Regulates MDSC function by increasing arginase activity and nitric oxide production and, in splenic MDSC, regulates arg1, CXCL12and IL16 | Up-regulation of miR-210 in ALL patients may potentiated immunosuppressive activity of tumour MDSCs | [40,41] |
| miR-223 | High expression in early thymocytes; down-regulation in DN2–DN3 stage | - | - | Down-regulation represses the differentiation and accumulation of MDSCs by targeting MEF2C |
Inhibits the expression of the tumour suppressor FBXW7 and induces T-ALL cell growth in a Notch-dependent manner | [42,43,44,45] |
| miR-325 | Controls T-cell proliferation and apoptosis by binding BAG2 | - | - | - | Low-expression enhances BAG2 levels in patients with T-ALL and promotes cancer cells proliferation | [46] |
| miR-483-3p | - | Involved in the development and cytolytic function of NK by modulating IGF-1 | - | - | Higher expression level plays a positive role in T-ALL pathophysiology | [47,48] |
| miR-653-5p | Enhances apoptosis and autophagy | - | - | - | Negatively regulated by circ-PRKD promotes T-ALL cell proliferation | [49] |
This table describes all the miRNAs that have been implicated in the immune response. It describes their expression and function in NK, T and Tregs, and MDSC cells and their deregulation in T-ALL. Keyword: miRNAs, Notch, T cells, Natural Killers (NK), T-regulatory cells (Tregs), Myeloid-derived suppressor cells (MDSCs), Acute Lymphoblastic Leukaemia (ALL), T-cell ALL (T-ALL); PD1: programmed death 1; PDL-1: programmed ligand death 1; DN: double negative; DP: double positive; SP: single positive; E2F1: E2F transcription factor 1; IL-2/IL-6/IL-10/IL-16/IL-17: Interleukin 2/6/10/16/17; DNMT3a/b: DNA (cytosine-5)-methyltransferase 3a/b; cAMP: cyclic adenosine monophosphate; PKA: proteinase Kinase A; PTEN: phosphatase and tensin homolog; SHIP1: Src homology 2 (SH2) domain-containing inositol polyphosphate 5′-phosphatase 1; mTOR: mechanistic target of rapamycin; SOCS1: suppressor of cytokine signalling 1; SMAD7: small mother against decapentaplegic; TGF-β: transforming growth factor beta; FOXP3: forkhead box P3; CXCL12: C-X-C motif chemokine 12; BAG2: BCL-2-associated athanogene; PRKD: protein kinase D; MEF2C: myocyte-specific enhancer factor 2C; IGF1: insulin-like growth factor 1.