Table 1.
Overview of diagnostic, prognostic and therapeutic potential of EVs in the context of haematological malignancies. The table illustrates the contribution of EVs to haematological malignancies and more specifically in their role as a biomarker, in disease outcomes, in drug resistance and as a therapeutic target. Furthermore, the associated EV cargo and resulting effect are demonstrated.
| EV Role | Target | Effect | Haematological Malignancy | Ref. |
|---|---|---|---|---|
| Biomarker | Upregulated miR-126-3p, miR-125a-5p, miR-199a-3p, miR-151a-3p and miR-423-5p, | - | MDS | [7] |
| Downregulated miR-16, miR-17, miR-20a, miR-21, miR-126, miR-181a, miR-146a, and miR-155 | - | MDS | [8] | |
| Downregulated miR-28 | Increased bleeding | MDS | [9] | |
| miR-10b | Suppressed myeloid differentiation and inhibited apoptosis | AML | [10] | |
| miR-150 and miR-155 | Suppressed proliferative and differentiation capacity of HSPC | AML | [11] | |
| miR-125b, miR-26a-5p | inhibited the Expression of proapoptotic molecules | AML | [12] | |
| lnc-RNA, such as circ-0009910 and circ-0004136 | Promote cell cycle progression and AML cell viability and invasion | AML | [13,14] | |
| DKK-1 | Inhibited osteogenesis | AML | [15] | |
| IL-8, VEGF | Stimulated angiogenesis | AML | [16] | |
| IL-10, IL-6, IL-17, NO, FOXP3 | Facilitated tumour survival | CML | [17] | |
| Dysregulation of miR-146b-5p | Associated with leukaemia transformation | CML | [18] | |
| miR-92a, miR-210, IL-8 | Promoted angiogenesis | CML | [19,20,21] | |
| miR-34a-5p, -miR-127-3p, miR-212-3p, miR-361 | Promoted survival and migration of CD34+ cells | MF | [22] | |
| Upregulation of miR-181b-5p | Promoted survival, migration and invasion of ALL cells | ALL | [23] | |
| Upregulation of survival genes and downregulation of proapoptotic genes via miR-181a | Leukaemic proliferation and survival | ALL | [24] | |
| miR-363 | Altered the function of CD4+ T cells | CLL | [25] | |
| Promote TNF-a/NFkB signalling | Altered ME to support tumour growth and survival | HL | [26] | |
| Elevated BCL-6 expression | - | DLBCL | [27] | |
| Upregulation of I/S molecules (such as iNOS) | Promote MDSCs and create I/S ME | MM | [28,29] | |
| miR-135b | Upregulation of HIF-1, which promoted angiogenesis | MM | [30] | |
| IncRUNX2-AS1 | Osteogenesis suppression | MM | [31] | |
| Increased AREG | Increased bone resorption | MM | [32] | |
| Increased CXCR4, RANKL, CTSK, MMP9, TRAP | Promoted osteoclast migration, differentiation, and survival | MM | [33] | |
| Drug resistance | TGF-β, miR-155, miR-375 | Stromal protection of AML cells | AML | [34] |
| miR-125b | - | APML | [35] | |
| MRP-1 | - | AML | [36] | |
| Galectin-3 | Protective effect of stromal fibroblasts on ALL cells | ALL | [37] | |
| Increased AKT mRNA | Reduced response to rituximab | FL | [27] | |
| miR-99a-5p and miR-125b-5p | Chemotherapy resistance and poor outcomes | HL | [38] | |
| Disease outcomes | Increased miR-125 | Aggressive course, higher risk of relapse and significantly shorter survival | AML | [39] |
| Increased miR-10b | Significantly shorter OS and DFS | AML | [10] | |
| Increased miR-1246, miR-532 and miR-125b | Predicted for relapse and poor outcomes | AML | [17,18,19,20,21,39,40,41,42,43,44,45,46] | |
| Elevated TF | Thrombotic events | MPD | [47] | |
| Elevated vWF and thrombin | Hypercoagulable state | ET | [48] | |
| BCL-6 and c-myc mRNA | Predict shorter OS and worse PFS | FL | [27] | |
| High levels of CD9/CD63 and PD-L1/CD63 EVs | Correlate with therapeutic failure and poor outcomes | DLBCL | [49] | |
| let-7b and miR-18a | Predicted for worse OS and PFS | MM | [50] | |
| Target | Antiapoptotic proteins (such as MCL-1, BCL-2 and BCL-XL) | Induction of apoptosis resistance | AML | [51] |
| Silencing of miR-181a | Inhibition of leukaemic cell proliferation | ALL | [24] | |
| EVs carrying gp350, CD40 and pp65 | Exhibited strong Ag-presenting capacity and induces specific cytotoxic T cells | CLL | [52] | |
| Exchanged Wnt signals between SP and non-SP cells | Allowed tumour cell communication and progression | HL | [26] | |
| Vaccine using TEX-carrying TAA | Enhanced antitumour responses in mouse models | Lymphoma | [53] | |
| Inhibition of EV formation | Amelioration of lytic lesions in mice | MM | [31] | |
| Melphalan- and doxorubicin-induced EVs | Carried IL15/IL15RA, which promotes an antitumour response | MM | [54] | |
| MSC-derived EVs | Reversed the bortezomib-induced bcl-2 inhibition and inhibit the cleavage of cas3, cas9 and PARP | MM | [55] |
Abbreviations: MDS: myelodysplastic syndrome, AML: acute myeloid leukaemia, HSPC: haematopoietic stem cell and progenitor cells, lnc-RNA: long noncoding RNA, DKK-1: dickkopf-related protein 1., VEGF: vascular endothelial growth factor, TGF-β: transforming growth factor-β, MRP-1: multidrug-resistant protein-1, OS: overall survival, DFS: disease-free survival, NO: nitric oxide, MPD: myeloproliferative disorders, TF: tissue factor, vWF: von Willebrand factor, ET: essential thrombocythaemia, MF: myelofibrosis, ALL: acute lymphoblastic leukaemia, CLL: chronic lymphocytic leukaemia, SP: side population, HL: Hodgkin lymphoma, TNF-a: tumour necrosis factor-a, ME: microenvironment, DLBCL: diffuse large B-cell lymphoma, FL: follicular lymphoma, PFS: progression-free survival, TEX: tumour-derived EVs, TAA: tumour-associated antigens, I/S: immunosuppressive, iNOS: inducible nitric oxide synthetase, MDSCs: myeloid-derived suppressor cells, MM: multiple myeloma, HIF-1: hypoxia-inducible factor 1, AREG: amphiregulin, cas3: caspase 3, PARP: poly (ADP-ribose) polymerase.