Ferroptosis is a nonapoptotic type of cell death characterized by an increase in lipid reactive oxygen species (ROS). Acute myeloid leukemia (AML)–derived bone marrow mesenchymal stem cells (AML-BMSCs) support the progression and drug resistance of AML by secreting various bioactive substances, including exosomes. However, the role of BMSCs in regulating lipid metabolism and ferroptosis in AML remains unexplored.
Results:
Exosomes secreted by AML-BMSCs increased the expression of miR-196a-5p in AML cells. MiR-196a-5p promoted the proliferation of AML cells, reduced lipid ROS and ferroptosis, and was associated with poor prognosis in AML patients. Mechanistically, miR-196a-5p inhibited the expression level of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L). Co-immunoprecipitation (CO-IP) analysis showed that NEDD4L was bound to long-chain acyl-CoA synthetase (ACSL)3 and promoted ubiquitin-mediated degradation of ACSL3 protein. In addition, we also demonstrated that AML-BMSCs highly expressed Ras-associated binding protein 7A (RAB7A), which was associated with exosomal miR-196a-5p release. Importantly, cytarabine (Ara-C) activated the expression of RAB7A and promoted the secretion of exosomal miR-196a-5p, which weakened the ubiquitination of ACSL3 by NEDD4L, leading to ferroptosis inhibition and Ara-C resistance in AML.
Innovation:
This is the first time that exosomes secreted by BMSCs (BMSCs-exos) have been linked to ferroptosis in AML cells, thereby expanding our understanding of the mechanism of drug resistance in AML cells. High miR-196a-5p expression reduced lipid ROS levels and ferroptosis in AML cells by inhibiting NEDD4L-mediated ubiquitination of ACSL3.
Conclusion:
This study identified a new network through which BMSCs-exos regulate ferroptosis in AML cells. We combined BMSCs and AML cells to provide new ideas for drug research targeting exosome secretion and ferroptosis. Antioxid. Redox Signal. 42, 933–953.
Get full access to this article
View all access options for this article.
References
1.
BandyopadhyayS, DuffyMP, AhnKJ, et al.Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging. Cell, 2024; 187(12):3120–3140.e29; doi: 10.1016/j.cell.2024.04.013
2.
Barrera-RamirezJ, LavoieJR, MagantiHB, et al.Micro-RNA profiling of exosomes from marrow-derived mesenchymal stromal cells in patients with acute myeloid leukemia: Implications in leukemogenesis. Stem Cell Rev Rep, 2017; 13(6):817–825; doi: 10.1007/s12015-017-9762-0
3.
BorellaG, Da RosA, BorileG, et al.Targeting the plasticity of mesenchymal stromal cells to reroute the course of acute myeloid leukemia. Blood, 2021; 138(7):557–570; doi: 10.1182/blood.2020009845
4.
CastaigneS, PautasC, TerréC, et al.; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo Acute Myeloid Leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet, 2012; 379(9825):1508–1516; doi: 10.1016/S0140-6736(12)60485-1
5.
CavalliG, HeardE. Advances in epigenetics link genetics to the environment and disease. Nature, 2019; 571(7766):489–499; doi: 10.1038/s41586-019-1411-0
6.
ChuM-Q, ZhangL-C, YuanQ, et al.Distinct associations of NEDD4L expression with genetic abnormalities and prognosis in acute myeloid leukemia. Cancer Cell Int, 2021; 21(1):615; doi: 10.1186/s12935-021-02327-7
7.
ConibearAC. Deciphering protein post-translational modifications using chemical biology tools. Nat Rev Chem, 2020; 4(12):674–695; doi: 10.1038/s41570-020-00223-8
8.
DaverNG, DailM, GarciaJS, et al.Venetoclax and idasanutlin in relapsed/refractory AML: A nonrandomized, open-label phase 1b trial. Blood, 2023; 141(11):1265–1276; doi: 10.1182/blood.2022016362
9.
DaverN, Garcia-ManeroG, BasuS, et al.Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: A nonrandomized, open-label, phase II study. Cancer Discov, 2019; 9(3):370–383; doi: 10.1158/2159-8290.CD-18-0774
10.
DixonSJ, LembergKM, LamprechtMR, et al.Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012; 149(5):1060–1072; doi: 10.1016/j.cell.2012.03.042
11.
DöhnerH, EsteyE, GrimwadeD, et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood, 2017; 129(4):424–447; doi: 10.1182/blood-2016-08-733196
12.
EsterbauerH, SchaurRJ, ZollnerH. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med, 1991; 11(1):81–128; doi: 10.1016/0891-5849(91)90192-6
13.
FahrigR, RuppM, Steinkamp-ZuchtA, et al.Use of primary rat and human hepatocyte sandwich cultures for activation of indirect carcinogens: Monitoring of DNA strand breaks and gene mutations in co-cultured cells. Toxicol In Vitro, 1998; 12(4):431–444; doi: 10.1016/S0887-2333(98)00005-8
14.
FanB, WangL, WangJ. RAB22A as a predictor of exosome secretion in the progression and relapse of multiple myeloma. Aging (Albany NY), 2024; 16(5):4169–4190; doi: 10.1863/2/aging.205565
15.
FargeT, SalandE, de ToniF, et al.Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov, 2017; 7(7):716–735; doi: 10.1158/2159-8290.CD-16-0441
16.
GeyhS, Rodríguez-ParedesM, JägerP, et al.Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia, 2016; 30(3):683–691; doi: 10.1038/leu.2015.325
17.
HassanzadehA, RahmanHS, MarkovA, et al.Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities. Stem Cell Res Ther, 2021; 12(1):297; doi: 10.1186/s13287-021-02378-7
18.
HoM, ChenT, LiuJ, et al.Targeting Histone Deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia, 2020; 34(1):196–209; doi: 10.1038/s41375-019-0493-x
19.
HouW, XieY, SongX, et al.Autophagy promotes ferroptosis by degradation of ferritin. Autophagy, 2016; 12(8):1425–1428; doi: 10.1080/15548627.2016.1187366
20.
JongsmaML, BakkerJ, CabukustaB, et al.SKIP-HOPS recruits TBC1D15 for a Rab7-to-Arl8b identity switch to control late endosome transport. Embo J, 2020; 39(6):e102301; doi: 10.1525/2/embj.2019102301
21.
KalluriR, LeBleuVS. The biology, function, and biomedical applications of exosomes. Science, 2020; 367(6478):eaau6977; doi: 10.1126/science.aau6977
22.
KalluriR, McAndrewsKM. The role of extracellular vesicles in cancer. Cell, 2023; 186(8):1610–1626; doi: 10.1016/j.cell.2023.03.010
23.
KhaldoyanidiS, NagorsenD, SteinA, et al.Immune biology of acute myeloid leukemia: Implications for immunotherapy. J Clin Oncol, 2021; 39(5):419–432; doi: 10.1200/JCO.20.00475
24.
KugeratskiFG, HodgeK, LillaS, et al.Quantitative proteomics identifies the core proteome of exosomes with syntenin-1 as the highest abundant protein and a putative universal biomarker. Nat Cell Biol, 2021; 23(6):631–641; doi: 10.1038/s41556-021-00693-y
25.
KumarB, GarciaM, WengL, et al.Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia, 2018; 32(3):575–587; doi: 10.1038/leu.2017.259
26.
LeP, SjD. Regulation of ferroptosis by lipid metabolism. Trends in Cell Biology, 2023; 33(12); doi: 10.1016/j.tcb.2023.05.003
27.
LiuJ, ChengY, ZhengM, et al.Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways. Signal Transduct Target Ther, 2021a;6(1):28; doi: 10.1038/s41392-020-00418-x
28.
LiuP, MaD, WangP, et al.Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2. Cell Death Dis, 2021b;12(1):20; doi: 10.1038/s41419-020-03331-x
29.
LuoM, WuL, ZhangK, et al.miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ, 2018; 25(8):1457–1472; doi: 10.1038/s41418-017-0053-8
30.
LyuT, WangY, LiD, et al.Exosomes from BM-MSCs promote acute myeloid leukemia cell proliferation, invasion and chemoresistance via upregulation of S100A4. Exp Hematol Oncol, 2021; 10(1):24; doi: 10.1186/s40164-021-00220-7
31.
MagtanongL, KoP-J, ToM, et al.Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol, 2019; 26(3):420–432.e9; doi: 10.1016/j.chembiol.2018.11.016
32.
MathieuM, Martin-JaularL, LavieuG, et al.Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol, 2019; 21(1):9–17; doi: 10.1038/s41556-018-0250-9
33.
Méndez-FerrerS, BonnetD, SteensmaDP, et al.Bone marrow niches in haematological malignancies. Nat Rev Cancer, 2020; 20(5):285–298; doi: 10.1038/s41568-020-0245-2
34.
NordmannM, CabreraM, PerzA, et al.The Mon1-Ccz1 complex is the GEF of the late endosomal Rab7 homolog Ypt7. Curr Biol, 2010; 20(18):1654–1659; doi: 10.1016/j.cub.2010.08.002
35.
PanC, HuT, LiuP, et al.BM-MSCs display altered gene expression profiles in B-cell acute lymphoblastic leukemia niches and exert pro-proliferative effects via overexpression of IFI6. J Transl Med, 2023; 21(1):593; doi: 10.1186/s12967-023-04464-1
36.
QiR, BaiY, LiK, et al.Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs. Drug Resist Updat, 2023; 68:100960; doi: 10.1016/j.drup.2023.100960
37.
QuX, LiuB, WangL, et al.Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer. Drug Resist Updat, 2023; 68:100936.
38.
QuanJ, BodeAM, LuoX. ACSL family: The regulatory mechanisms and therapeutic implications in cancer. Eur J Pharmacol, 2021; 909:174397; doi: 10.1016/j.ejphar.2021.174397
RothA, SingerT. The application of 3D cell models to support drug safety assessment: Opportunities & challenges. Adv Drug Deliv Rev, 2014; 69–70:179–189; doi: 10.1016/j.addr.2013.12.005
42.
SaatciO, AlamR, Huynh-DamK-T, et al.Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer. Cell Death Dis, 2024; 15(6):418; doi: 10.1038/s41419-024-06814-3
43.
SaitoK, ZhangQ, YangH, et al.Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition. Blood Adv, 2021; 5(20):4233–4255; doi: 10.1182/bloodadvances.2020003661
44.
SchneiderC, HilbertJ, GenevauxF, et al.A novel AMPK inhibitor sensitizes pancreatic cancer cells to ferroptosis induction. Adv Sci (Weinh), 2024; 11(31):e2307695; doi: 10.1002/advs.202307695
45.
ShafferBC, GilletJ-P, PatelC, et al.Drug resistance: Still a daunting challenge to the successful treatment of AML. Drug Resist Updat, 2012; 15(1–2):62–69; doi: 10.1016/j.drup.2012.02.001
46.
ShiY, FangN, WuY, et al.NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression. Cell Commun Signal, 2024; 22(1):302; doi: 10.1186/s12964-024-01685-9
47.
StockwellBR, Friedmann AngeliJP, BayirH, et al.Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017; 171(2):273–285; doi: 10.1016/j.cell.2017.09.021
48.
TangD, ChenX, KangR, et al.Ferroptosis: Molecular mechanisms and health implications. Cell Res, 2021; 31(2):107–125; doi: 10.1038/s41422-020-00441-1
49.
UbellackerJM, TasdoganA, RameshV, et al.Lymph protects metastasizing melanoma cells from ferroptosis. Nature, 2020; 585(7823):113–118; doi: 10.1038/s41586-020-2623-z
50.
ValadiH, EkströmK, BossiosA, et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol, 2007; 9(6):654–659; doi: 10.1038/ncb1596
51.
VerweijFJ, BebelmanMP, GeorgeAE, et al.ER membrane contact sites support endosomal small GTPase conversion for exosome secretion. J Cell Biol, 2022; 221(12):e202112032; doi: 10.1083/jcb.202112032
52.
WangW, GreenM, ChoiJE, et al.CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature, 2019; 569(7755):270–274; doi: 10.1038/s41586-019-1170-y
53.
WangJ, HendrixA, HernotS, et al.Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood, 2014; 124(4):555–566; doi: 10.1182/blood-2014-03-562439
54.
WangN, MaT, YuB. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct Target Ther, 2023; 8(1):69; doi: 10.1038/s41392-023-01341-7
WeiY, LiuW, WangR, et al.Propionate promotes ferroptosis and apoptosis through mitophagy and ACSL4-mediated ferroptosis elicits anti-leukemia immunity. Free Radic Biol Med, 2024; 213:36–51; doi: 10.1016/j.freeradbiomed.2024.01.005
57.
WuS, LuoM, ToKKW, et al.Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer. Mol Cancer, 2021; 20(1):17; doi: 10.1186/s12943-021-01307-9
58.
XuS, CaoB, XuanG, et al.Function and regulation of Rab GTPases in cancers. Cell Biol Toxicol, 2024; 40(1):28; doi: 10.1007/s10565-024-09866-5
59.
YanR, LiuD, GuoH, et al.LAPTM4B counteracts ferroptosis via suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer. Cell Death Dis, 2024; 15(6):436; doi: 10.1038/s41419-024-06836-x
60.
YuanY, TanS, WangH, et al.Mesenchymal stem cell-derived exosomal miRNA-222-3p increases Th1/Th2 ratio and promotes apoptosis of acute myeloid leukemia cells. Anal Cell Pathol (Amst), 2023; 2023:4024887; doi: 10.1155/2023/4024887
61.
ZengD, YeZ, ShenR, et al.IOBR: Multi-omics immuno-oncology biological research to decode tumor microenvironment and signatures. Front Immunol, 2021; 12:687975; doi: 10.3389/fimmu.2021.687975
62.
ZhangH, DengT, LiuR, et al.CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer, 2020; 19(1):43; doi: 10.1186/s12943-020-01168-8
63.
ZhangL, ZhaoQ, CangH, et al.Acute myeloid leukemia cells educate mesenchymal stromal cells toward an adipogenic differentiation propensity with leukemia promotion capabilities. Adv Sci (Weinh), 2022; 9(16):2105811; doi: 10.1002/advs.202105811
64.
ZhongQ, XiaoX, QiuY, et al.Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications. MedComm (2020), 2023; 4(3):e261; doi: 10.1002/mco2.261
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
