Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression
Abstract
:1. Introduction
2. Extracellular Vesicles
3. The Leukaemia Heist: Niche Remodelling Favours Disease Progression
3.1. Leukaemic Stem Cell Inception
3.2. Self-Sustained Leukaemia Growth
Factor | Origin | Target | Signalling | Pro-Leukaemia Effect | Cancer Hallmark [20] | Ref. | Sample Origin |
---|---|---|---|---|---|---|---|
LEUKAEMIA SELF-SUFFICIENCY | |||||||
Gal-9 | LSCs | LSCs | Autocrine | Promote LSC self-renewal through activation of NF-kB and Wnt pathways, by Gal-9/TIM-3 binding. | Enabling replicative immortality | [41] | Patient Sample |
TNF-α | LSCs | LSCs | Autocrine | Promote LSC self-renewal through increase in NF-kB pathway activity in positive feedback loop. | Enabling replicative immortality | [43] | Mouse BM |
IL1-β | LSCs | LSCs | Autocrine | Promote LSC self-renewal through increase in NF-kB pathway activity and increase in HGFs, GM-CSF, IL-6, and TNF-α production, creating a positive feedback loop of proliferative signalling. | Enabling replicative immortality | [45] | Patient Sample |
NmU | LSC | LSC | Autocrine | Promote leukaemic cell growth and proliferation through MYB-related mechanism. | Sustaining proliferative signalling | [46] | K562 AML Line, Patient Sample |
miR-221- 3p | AML Cells | AML Cells | Autocrine EV Cargo | Promote leukaemic cell growth and proliferation through promoting entry into cell cycle and apoptosis inhibition through downregulation of Gpb2 gene expression. | Resisting cell death | [49] | Mouse Model THP-1, HL-60, Kasumi-1, MOLM-13 (AML Cell Lines) |
ENDOSTEAL NICHE | |||||||
IL-8 | HSCs, BMMSCs | LSCs | Soluble Factor | Lead to induction of proliferative and oncogenic pathways and recruitment of myeloid-derived suppressor cells through binding to overexpressed CXCR1 and CXCR2 receptors. | Sustaining proliferative signalling | [50] | Patient Sample |
MIF | AML Blasts | BMMSCs | Soluble Factor | Induce IL-8 secretion in PKCβ-regulated mechanism. | Sustaining proliferative signalling | [51] | Patient Sample |
IL-6 | BMMSCs | AML cells | Soluble Factor | Promote chemoresistance in leukaemic cells through STAT-3 pathway activation, leading to higher OXPHOS levels. | Resisting cell death | [52] | HS-5 (BMMSC lines) HL-60, U-937,THP-1 (AML lines) |
TPO | Niche Osteoblasts, HSCs, LSCs | HSCs and LSCs | EV Cargo | Induce HSC adhesion to osteoblastic niche. Promote SC quiescence and induce SC proliferation in endosteal niche. | Enabling replicative immortality | [53,54] | Mouse BM |
ANGPTL3 | Endothelial cells, BMMSCs, HSCs, LSCs | HSCs and LSCs | EV Cargo | Directly bind to HSCs. Promote SC quiescence through suppression of TF Ikaros. | Enabling replicative immortality | [53,55] | Mouse BM |
miR-34c-5p | LSCs | None, exported out of LSCs via EVs | EV Cargo | miR-34c-5p induces LSC senescence through p53/p21-dependent CDK/Cyclin or p53-independent CDK/Cyclin pathways. LSC EV-mediated export of this factor inhibits this effect, leading to worse AML prognosis. | Senescent cells evading growth suppressors | [56] | Patient Sample |
miR-1246 | AML Cells | LSCs | EV Cargo | Activate STAT3 pathway through LRIGH1 downregulation. Increase LSC viability and proliferation. Decrease LSC differentiation and apoptosis. | Resisting cell death | [57] | KG1-A, Kasumi-1 (AML lines) |
IFN-γ | BMMSCs, AML cells | BMMSCs, HSCs and LSCs | Soluble factor EV Cargo | Pro-inflammatory effects. Activate STAT1 signalling to induce oxidative stress, by increased ROS production, leading to decreased osteogenic differentiation of MSCs. Decrease immune response to LSCs by conditioning MSCs into anti-inflammatory activity as a response to excess IFN-γ. | Tumour promoting inflammation Avoiding immune destruction | [58,59] | Patient Sample |
PGE2 TGF-β TSG-6 HGF HLA-G6 IL-10 IL-6 galectins | BMMSCs | Many | Soluble factor EV Cargo | Dampen immune response against LSCs through promoting anti-inflammatory environment as response to excess inflammatory factors produced by AML cells. | Avoiding immune destruction | [60,61,62] | Patient Sample [60,62] Mouse BM [61] Mouse MS-5 Stromal Line [62] |
miR-188-5p | LSCs | BMMSCs | EV Cargo | Promote LSC proliferation through restructuring of niche MSCs, as they increase MCAM presence on their surface, increasing binding to myeloid cells, leading to ERK signalling pathway activation. | Sustaining proliferative signalling | [63] | KG1a, SKM-1 (AML Lines) HS5, HS27a (BMMSC lines) |
miR-4532 | AML Blasts | Pre-Osteoblasts | EV Cargo | Increase DKK1 expression, which inhibits Wnt pathway signalling, leading to decrease in osteoblastic differentiation, causing disruption of endosteal niche bone formation and normal haematopoiesis. | Activating invasion | [64,65] | HL-60, Molm-14, OCI-AML3 (AML lines) |
PRDX2 PRDX4 L-plastin | Erythroleukaemia Cells | Osteoclast precursors | EV Cargo | Promote bone resorption through induction of osteoclast differentiation. Bone resorption increases the central marrow cavity space, where AML cell growth can occur. | Activating invasion | [66,67,68] | Mouse BM Human Breast Cancer lines |
YBX1 | AML Cells | BMMSCs | EV Cargo | Reduces osteoblastic differentiation, disrupting normal haematopoiesis. YBX1 downregulation led to impact on other EV cargo, hinting at possible cooperation between different factors. | Activating invasion | [69] | K562, MV-4–11 (AML Lines) Patient Sample (BMMSC) |
FTO | BMMSCs | AML Blasts | EV Cargo | Increased LncRNA GLCC1 expression in AML blasts, leading to increase in LncRNA-GLCC1-IGF2BP1-c-Myc signalling pathway activation, linked with higher tumour aggressiveness. | Sustaining proliferative signalling | [70] | THP-1, Kasumi-1 (AML Lines) Patient Sample (BMMSC) |
AML derived EVs | AML Cells | BMMSCs | EVs | Alter gene expression profile of BMMSCs, with concentration-dependent effects. Increased MSC survival, proliferation, and metabolic activity through increased Ki-67 and BCL2 expression (at lower concentrations of AML cell-derived EVs). Downregulation of ROS production. Upregulation of apoptosis (at higher AML cell-derived EV concentrations). | Resisting cell death | [71] | Patient Sample |
VASCULAR NICHE | |||||||
CXCL12 (SDF-1) | BMMSCs | AML Cells | Soluble Factor EV Cargo | Bind to CXCR4 expressed on AML cells to promote homing to BM niche and stromal cell–AML cell adhesion. Increase AML cell resistance to apoptosis. Promote LSC quiescence, maintenance, and proliferation. | Activating invasion Resisting cell death | [72,73,74] | Patient Sample (BMMSCs) KG-1a (AML Line) [72] Mouse BM [74] |
ANGPL2 | Endothelial Cells | LSCs | EV Cargo | Bind to LILRB2 receptor to promote LSC maintenance and drive LSCs to localize around endothelial cells in BM niche. | Enabling replicative immortality | [75] | Mouse Model |
VEGF VEGFR | AML Cells | Endothelial Cells | EV Cargo | Promote vascular remodelling and angiogenesis. | Inducing or accessing vasculature | [25] | Patient Sample HUVECs |
IGF-1R coding mRNA | AML Cells | BMMSCs | EV Cargo | Promote IGF-1R expression, which increases VEGF secretion, leading to increased angiogenesis and proliferation. | Inducing or accessing vasculature | [76] | HEL, HL-60, Molm-14, U937 (AML Lines) Patient Samples |
miR-92a | AML Cells | Endothelial Cells | EV Cargo | Promote endothelial cell migration and tube formation, but not growth. Decrease expression of the pro-angiogenic Integrin-α5. | Inducing or accessing vasculature | [77] | K562 AML Line HUVECs |
miR-3064-3p miR-339-5p miR-3622a-5p | AML Cells | Endothelial Cells | EV Cargo | Promote angiogenesis in HUVECs, regulated by P62 expression. | Inducing or accessing vasculature | [78] | U937 AML Line HUVECs |
CXCL12 SCF IL-7 IL-15 M-CSF BMP-4 CCL-2 | BM Adipocytes | BMMSCs | Soluble Factors | Promote HSC proliferation and haematopoietic regeneration, upregulated and hijacked in AML. | Sustaining proliferative signalling | [79] | Mouse Model |
GDF15 | AML Cells | BM Adipocytes | Soluble Factor | Induce lipolysis in BM adipocytes, releasing fatty acids (FAs) into the vascular environment. FAs are uptaken by AML blasts via an FABP4-dependent mechanism and used as an energy source. | Deregulating cellular metabolism | [80] | THP-1, K562, HEL, HL-60 and Kasumi AML Lines Patient Sample (BMMSCs) differentiated into Adipocytes |
IL-8 CCL2 TIMP-1 TIMP-2 VEGF-D | ADSCs | Endothelial Cells | EV Cargo | Induce tube formation and angiogenesis. | Inducing or accessing vasculature | [81] | Canine adipose tissue sample SVEC-4 Mouse endothelial line |
miR-155-5p miR-106a-5p miR-106b-5p miR130b-3p miR-16-5p miR-181a-5p miR-19b-3p miR-466k miR-93-5p miR-126a-5p | AML Cells | HPSCs | EV Cargo | Induce activation of inflammatory secretion profiles in HPSCs, leading to increased AML progression. | Avoiding immune destruction | [82] | C1498 Mouse AML Line Mouse Model |
UNKNOWN MECHAMISM | |||||||
MPIF-1 (CCL23) | Unknown | Found in blood plasma | Soluble Factor | Found at elevated levels in AML patient plasma. MPIF has reported to inhibit proliferation and differentiation of myeloid progenitors, but role in AML has not been described. | Unknown | [83] | Patient Sample |
BMP10 CCL3 CX3CL1 OPN CD105 PTHLH CHRDL1 MMP7 | Many | Found in blood plasma | Soluble Factors | Found at elevated levels in AML patient plasma. Factors linked with bone homeostasis through multiple different pathways. Potential coordinated mechanism of action in BM niche activity in AML | Unknown | [83] | Patient Sample |
CD31/endomucin-expressing cellular debris particles | Endothelium | Found in vascular lumen | EVs | Particles of endothelial EV origin found in the vasculature of leukaemic mice, but not in healthy control specimens, suggesting it is a possible risk factor. | Unknown | [84] | Mouse model |
3.3. Rewiring the Haematopoietic Niches for LSC Traction
3.3.1. Endosteal Niche Remodelling
BM Mesenchymal Stromal/Stem Cells
Osteoprogenitors, Bone Lining Cells, and Osteoclasts
3.3.2. Vascular Niche Remodelling
Endothelial Cells and Progenitors
Adipocytes
Sympathetic Neurons
4. Emerging Organ-on-a-Chip Technologies to Unravel EV Signalling Networks
5. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Mendes, M.; Monteiro, A.C.; Neto, E.; Barrias, C.C.; Sobrinho-Simões, M.A.; Duarte, D.; Caires, H.R. Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression. Int. J. Mol. Sci. 2024, 25, 4430. https://doi.org/10.3390/ijms25084430
Mendes M, Monteiro AC, Neto E, Barrias CC, Sobrinho-Simões MA, Duarte D, Caires HR. Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression. International Journal of Molecular Sciences. 2024; 25(8):4430. https://doi.org/10.3390/ijms25084430
Chicago/Turabian StyleMendes, Manuel, Ana C. Monteiro, Estrela Neto, Cristina C. Barrias, Manuel A. Sobrinho-Simões, Delfim Duarte, and Hugo R. Caires. 2024. "Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression" International Journal of Molecular Sciences 25, no. 8: 4430. https://doi.org/10.3390/ijms25084430