Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute myeloid leukemia cell-derived extracellular vesicles carrying microRNA-548ac regulate hematopoietic function via the TRIM28/STAT3 pathway

Cancer Gene Therapy volume 29, pages 918–929 (2022)Cite this article

Subjects

Abstract

microRNAs (miRNAs or miRs) can be delivered from acute myeloid leukemia (AML) cells to hematopoietic stem cells (HSCs) to regulate hematopoietic function via extracellular vesicles (EVs). In this study, we investigated the roles played by EVs that transport miR-548ac from AML cells in normal hematopoiesis. Bioinformatics analysis demonstrated that miR-548ac was highly expressed in AML-derived EVs. The expression of miR-548ac and TRIM28 and the targeting relationship were identified, and the results demonstrated that the expression of miR-548ac was upregulated in AML cell lines and AML cell-secreted EVs compared with CD34+ HSCs. AML-derived EVs targeted CD34+ HSCs to induce decreased expression of TRIM28 and downstream activation of STAT3. Exosomal miR-548ac was transferred into CD34+ HSCs to target TRIM28. Through gain- and loss-of-function assays, it was observed that the abrogated expression of miR-548ac or STAT3 promoted colony-forming units (CFU), whereas overexpressed miR-548ac repressed CFU, which was rescued by overexpression of TRIM28. Taken together, these results indicated that miR-548ac delivered by AML cell-derived EVs inhibits hematopoiesis via TRIM28-dependent STAT3 activation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: miR-548ac is abundant in EVs derived from AML cells.
Fig. 2: EVs derived from AML HL-60 cells targeted HSCs.
Fig. 3: miR-548ac delivered by AML HL-60 cell-derived EVs targets HSCs.
Fig. 4: miR-548ac delivered by AML HL-60 cell-derived EVs may function in AML by targeting TRIM28.
Fig. 5: miR-548ac delivered by AML HL-60 cell-derived EVs inhibits hematopoietic function by targeting TRIM28.
Fig. 6: miR-548ac abrogates the hematopoietic function of CD34+ HSCs by TRIM28-activated STAT3.
Fig. 7: Silencing of miR-548ac in EVs inhibits the growth of AML stem cells in tumor xenograft models.
Fig. 8: Serum EV-derived miR-548ac can be used as a predictor of AML.
Fig. 9: Map depicting the mechanism by which miR-548ac from AML cell-released EVs affected the progression of AML.

Similar content being viewed by others

References

  1. Wouters BJ, Delwel R. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 2016;127:42–52.

    Article  CAS  Google Scholar 

  2. Lehrnbecher T, Sung L. Anti-infective prophylaxis in pediatric patients with acute myeloid leukemia. Expert Rev Hematol. 2014;7:819–30.

    Article  CAS  Google Scholar 

  3. Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29:475–86.

    Article  CAS  Google Scholar 

  4. Ye M, Zhang H, Yang H, Koche R, Staber PB, Cusan M, et al. Hematopoietic differentiation is required for initiation of acute myeloid leukemia. Cell Stem Cell. 2015;17:611–23.

    Article  CAS  Google Scholar 

  5. Lim Z, Brand R, Martino R, van Biezen A, Finke J, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010;28:405–11.

    Article  Google Scholar 

  6. Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest. 2016;126:1139–43.

    Article  Google Scholar 

  7. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.

    Article  Google Scholar 

  8. Xu R, Rai A, Chen M, Suwakulsiri W, Greening DW, Simpson RJ. Extracellular vesicles in cancer - implications for future improvements in cancer care. Nat Rev Clin Oncol. 2018;15:617–38.

    Article  CAS  Google Scholar 

  9. Gargiulo E, Paggetti J, Moussay E. Hematological malignancy-derived small extracellular vesicles and tumor microenvironment: the art of turning foes into friends. Cells. 2019;8:511.

    Article  CAS  Google Scholar 

  10. Marcucci G, Mrozek K, Radmacher MD, Garzon R, Bloomfield CD. The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 2011;117:1121–9.

    Article  CAS  Google Scholar 

  11. Hornick NI, Doron B, Abdelhamed S, Huan J, Harrington CA, Shen R, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal. 2016;9:ra88.

    Article  Google Scholar 

  12. Wolf D, Goff SP. TRIM28 mediates primer binding site-targeted silencing of murine leukemia virus in embryonic cells. Cell 2007;131:46–57.

    Article  CAS  Google Scholar 

  13. Kamitani S, Togi S, Ikeda O, Nakasuji M, Sakauchi A, Sekine Y, et al. Kruppel-associated box-associated protein 1 negatively regulates TNF-alpha-induced NF-kappaB transcriptional activity by influencing the interactions among STAT3, p300, and NF-kappaB/p65. J Immunol. 2011;187:2476–83.

    Article  CAS  Google Scholar 

  14. King CA. Kaposi’s sarcoma-associated herpesvirus kaposin B induces unique monophosphorylation of STAT3 at serine 727 and MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28. J Virol. 2013;87:8779–91.

    Article  CAS  Google Scholar 

  15. Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood 2011;117:5701–9.

    Article  CAS  Google Scholar 

  16. Kanna R, Choudhary G, Ramachandra N, Steidl U, Verma A, Shastri A. STAT3 inhibition as a therapeutic strategy for leukemia. Leuk Lymphoma. 2018;59:2068–74.

    Article  CAS  Google Scholar 

  17. Wallace JA, O’Connell RM. MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts. Blood 2017;130:1290–301.

    Article  CAS  Google Scholar 

  18. Huang Q, Wang L, Ran Q, Wang J, Wang C, He H, et al. Notopterol-induced apoptosis and differentiation in human acute myeloid leukemia HL-60 cells. Drug Des Dev Ther. 2019;13:1927–40.

    Article  CAS  Google Scholar 

  19. Nikkhah H, Safarzadeh E, Shamsasenjan K, Yousefi M, Lotfinejad P, Talebi M, et al. The effect of bone marrow mesenchymal stem cells on the granulocytic differentiation of HL-60 cells. Turk J Hematol. 2018;35:42–48.

    Article  CAS  Google Scholar 

  20. Bak RO, Dever DP, Porteus MH. CRISPR/Cas9 genome editing in human hematopoietic stem cells. Nat Protoc. 2018;13:358–76.

    Article  CAS  Google Scholar 

  21. Kornafel T, Tsao EY, Sabelhaus E, Surges L, Apkon SD. Physical and occupational therapy for a teenager with acute flaccid myelitis: a case report. Phys Occup Ther Pediatr. 2017;37:485–595.

    Article  Google Scholar 

  22. Bill MA, Fuchs JR, Li C, Yui J, Bakan C, Benson DM Jr., et al. The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with antitumor activity. Mol Cancer. 2010;9:165.

    Article  Google Scholar 

  23. Hosoya T, Clifford M, Losson R, Tanabe O, Engel JD. TRIM28 is essential for erythroblast differentiation in the mouse. Blood 2013;122:3798–807.

    Article  CAS  Google Scholar 

  24. Tsuruma R, Ohbayashi N, Kamitani S, Ikeda O, Sato N, Muromoto R, et al. Physical and functional interactions between STAT3 and KAP1. Oncogene 2008;27:3054–9.

    Article  CAS  Google Scholar 

  25. Shastri A, Choudhary G, Teixeira M, Gordon-Mitchell S, Ramachandra N, Bernard L, et al. Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. J Clin Invest. 2018;128:5479–88.

    Article  Google Scholar 

  26. De Kouchkovsky I, Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update’. Blood Cancer J. 2016;6:e441.

    Article  Google Scholar 

  27. Duarte D, Hawkins ED, Akinduro O, Ang H, De Filippo K, Kong IY, et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell. 2018;22:64–77. e66

    Article  CAS  Google Scholar 

  28. Litwinska Z, Luczkowska K, Machalinski B. Extracellular vesicles in hematological malignancies. Leuk Lymphoma. 2019;60:29–36.

    Article  CAS  Google Scholar 

  29. Murillo OD, Thistlethwaite W, Rozowsky J, Subramanian SL, Lucero R, Shah N, et al. exRNA atlas analysis reveals distinct extracellular RNA cargo types and their carriers present across human biofluids. Cell 2019;177:463–77. e415

    Article  CAS  Google Scholar 

  30. Boyiadzis M, Whiteside TL. Exosomes in acute myeloid leukemia inhibit hematopoiesis. Curr Opin Hematol. 2018;25:279–84.

    Article  CAS  Google Scholar 

  31. Kotaki R, Koyama-Nasu R, Yamakawa N, Kotani A. miRNAs in normal and malignant hematopoiesis. Int J Mol Sci. 2017; 18:1495.

  32. Zhao C, Du F, Zhao Y, Wang S, Qi L. Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway. Stem Cell Res Ther. 2019;10:384.

    Article  CAS  Google Scholar 

  33. Czerwinska P, Mazurek S, Wiznerowicz M. The complexity of TRIM28 contribution to cancer. J Biomed Sci. 2017;24:63.

    Article  Google Scholar 

  34. Barde I, Rauwel B, Marin-Florez RM, Corsinotti A, Laurenti E, Verp S, et al. A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy. Science 2013;340:350–3.

    Article  CAS  Google Scholar 

  35. Qi Z, Cai S, Cai J, Chen L, Yao Y, Chen L, et al. miR-491 regulates glioma cells proliferation by targeting TRIM28 in vitro. BMC Neurol. 2016;16:248.

    Article  Google Scholar 

  36. Oh IH, Eaves CJ. Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity. Oncogene 2002;21:4778–87.

    Article  CAS  Google Scholar 

  37. Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18:254–67.

    Article  CAS  Google Scholar 

  38. Ogura M, Uchida T, Terui Y, Hayakawa F, Kobayashi Y, Taniwaki M, et al. Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci. 2015;106:896–901.

    Article  CAS  Google Scholar 

  39. Reilley MJ, McCoon P, Cook C, Lyne P, Kurzrock R, Kim Y, et al. STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial. J Immunother Cancer. 2018;6:119.

    Article  Google Scholar 

Download references

Funding

This work was supported by the Foundation of Science and Technology Department of Jilin Province (20190101006JH, 20200404175YY), Foundation of the Education Department of Jilin Province (no. JJKH20200462KJ), Foundation of Health and Family Planning Commission of Jilin Province (no. 2019J066), Foundation of the Administration of Traditional Chinese Medicine of Jilin Province (no. 2019138), Foundation of Suzhou Institute of medical engineering, Chinese Academy of Sciences-Jilin Science and technology cooperation project (no. E0550101), Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University (no. 20180623045TC).

Author information

Author notes

  1. These authors contributed equally: Chen Zhao and Yang Zhao.

Authors and Affiliations

  1. Department of Preventive Medicine, Jilin Medical University, Jilin, P.R. China

    Chen Zhao

  2. Department of Emergency and Intensive Medicine, No. 965 Hospital of PLA Joint Logistic Support Force, Jilin, China

    Yang Zhao

  3. Medical Technology College of Beihua University, Jilin, P.R. China

    Jiaqi Zhao

  4. Department of Laboratory Medicine, Jilin Medical University, Jilin, P.R. China

    Guixian Meng, Shuyu Huang & Yichen Liu

  5. Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, China

    Shanshan Wang

  6. Department of Pathophysiology, Jilin Medical University, Jilin, China

    Ling Qi

  7. The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China

    Ling Qi

Authors
  1. Chen Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiaqi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guixian Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuyu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yichen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shanshan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ling Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ling Qi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, C., Zhao, Y., Zhao, J. et al. Acute myeloid leukemia cell-derived extracellular vesicles carrying microRNA-548ac regulate hematopoietic function via the TRIM28/STAT3 pathway. Cancer Gene Ther 29, 918–929 (2022). https://doi.org/10.1038/s41417-021-00378-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-021-00378-6

This article is cited by

Search

Advanced search

Quick links