Skip to main content

Advertisement

SpringerLink
Log in

ARID1A has prognostic value in acute myeloid leukemia and promotes cell proliferation via TGF-β1/SMAD3 signaling

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Previous studies have shown that the gene AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of SWI/SNF chromatin remodeling complex that acts as a tumor suppressor gene in several cancers and plays a vital role in tumorigenesis. However, its biological functions in acute myeloid leukemia (AML) are still unclear. Here, we tried to elaborate the expression of ARID1A in patients with AML, in leukemia cells, as well as the molecular mechanisms. Our results indicated that the expression of ARID1A was significantly downregulated in the bone marrow of patients with AML and relapsed patients compared with healthy subjects and patients in complete remission. Meantime, receiver operating characteristic curve analysis showed that the expression of ARID1A could be used to discriminate between patients with AML and patients in complete remission. We further constructed a knockdown cell model to determine the regulatory mechanisms of ARID1A in AML cells. We found that the decreased expression of ARID1A promoted cell proliferation, suppressed cellular apoptosis, and impeded cell cycle arrest via TGF-β1/SMAD3 signaling pathway. These results revealed that the reduced expression of ARID1A promoted cell proliferation via the TGF-β1/SMAD3 cascade and served as a prognostic biomarker for AML and therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Short N, Rytting M, Cortes JJL. Acute myeloid leukaemia. Lancet. 2018;392(10147):593–606.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lichtenegger FS, Krupka C, et al. Immunotherapy for acute myeloid leukemia. Semin Hamatol. 2015;52(3):207–14.

    Article  CAS  Google Scholar 

  3. Vago L, Gojo I. Immune escape and immunotherapy of acute myeloid leukemia. J Clin Investig. 2020;130(4):1552–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bradstock K, Link E, Di Iulio J, et al. Idarubicin dose escalation during consolidation therapy for adult acute myeloid leukemia. J Clin Oncol. 2017;35(15):1678–85.

    Article  CAS  PubMed  Google Scholar 

  5. Carter J, Hege K, Yang J, et al. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther. 2020;5(1):288.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bertoli S, Tavitian S, Huynh A, et al. Improved outcome for AML patients over the years 2000–2014. Blood Cancer J. 2017;7(12):635.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tyner JW, Tognon CE, Bottomly D, et al. Functional genomic landscape of acute myeloid leukaemia. J Nat. 2018;562(7728):526–31.

    Article  CAS  Google Scholar 

  8. Bochtler T, Fröhling S, Krämer AJL. Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia. Leukimia. 2015;29(6):1243–52.

    Article  CAS  Google Scholar 

  9. Ley YJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059.

    Article  PubMed  Google Scholar 

  10. Issa G, Ravandi F, DiNardo C, et al. Therapeutic implications of menin inhibition in acute leukemias. Leukemia. 2021;35(9):1–14.

    Article  Google Scholar 

  11. Katerndahl C, Rogers O, Day R, et al. Tumor suppressor function of Gata2 in acute promyelocytic leukemia. Blood. 2021;138:1148–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Agrawal-Singh S, Isken F, Agelopoulos K, et al. Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene. Blood. 2012;119(10):2346–57.

    Article  CAS  PubMed  Google Scholar 

  13. Agrawal S, Hofmann WK, Tidow N, et al. The C/EBPδ tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood. 2007;109(9):3895–905.

    Article  CAS  PubMed  Google Scholar 

  14. Wilson B, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011;11(7):481–92.

    Article  CAS  PubMed  Google Scholar 

  15. Mohrmann L, Langenberg K, Krijgsveld J, et al. Differential targeting of two distinct SWI/SNF-related Drosophila chromatin-remodeling complexes. Mol Cell Biol. 2004;24(8):3077–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang X, Haswell J, Roberts CW. Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer—mechanisms and potential therapeutic insights. Clin Cancer Res. 2014;20(1):21–7.

    Article  PubMed  Google Scholar 

  17. Masliah-Planchon J, Bièche I, Guinebretière J, et al. SWI/SNF chromatin remodeling and human malignancies. Annu Rev Pathol. 2015;10(1):145–71.

    Article  CAS  PubMed  Google Scholar 

  18. Guan B, Wang T, Lem S. ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res. 2011;71(21):6718–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guan B, Rahmanto Y, Wu R, et al. Roles of deletion of ARID1A, a tumor suppressor, in mouse ovarian tumorigenesis. J Natl Cancer Inst. 2014;106(7):766–76.

    Article  Google Scholar 

  20. Wu J, Roberts CW. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 2013;3(1):35–43.

    Article  CAS  PubMed  Google Scholar 

  21. Wiegand K, Shah S, Al-Agha O, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363(16):1532–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tokunaga R, Xiu J, Goldberg R, et al. The impact of ARID1A mutation on molecular characteristics in colorectal cancer. Eur J Cancer. 2020;140:119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mayes K, Qiu Z, Alhazmi A, et al. ATP-dependent chromatin remodeling complexes as novel targets for cancer therapy. Adv Cancer Res. 2014;121(20):183–233.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nagl N, Patsialou A, Haines D, et al. The p270 (ARID1A/SMARCF1) subunit of mammalian SWI/SNF-related complexes is essential for normal cell cycle arrest. Cancer Res. 2005;65(20):9236–44.

    Article  CAS  PubMed  Google Scholar 

  25. Park Y, Chui M, Suryo Rahmanto Y, et al. Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy. Clin Cancer Res. 2019;25(18):5584–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Madan V, Shyamsunder P, Han L, et al. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Leukemia. 2016;30(12):2430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stratmann S, Yones SA, Mayrhofer M, et al. Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets. Blood Adv. 2021;5(3):900–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Culp-Hill R, D’Alessandro A, Pietras EM. Extinguishing the embers: targeting AML metabolism. Trends Mol Med. 2021;27(4):332–44.

    Article  CAS  PubMed  Google Scholar 

  29. Han L, Madan V, Mayakonda A, et al. Chromatin remodeling mediated by ARID1A is indispensable for normal hematopoiesis in mice. Leukemia. 2019;33(9):2291–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nagarajan S, Rao S, Sutton J, et al. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat Genet. 2020;52(2):187–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schepers K, Campbell T, Passegue E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell. 2015;16(13):254–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jäger P, Geyh S, Twarock S, et al. Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells. Stem Cells. 2021;39:1270–84.

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by medical and health development Foundation of Shandong Province (No. 2018WS420) and Natural Science Foundation of Shandong Province (No. ZR2017MH009 and No. ZR2021MH215).

Author information

Authors and Affiliations

  1. Zhong Yuan Academy of Biological Medicine, Liaocheng People’s Hospital, Liaocheng, 252000, Shandong, People’s Republic of China

    Tianying Ren, Dongliang Chen, Shuang Wang & Dawei Yang

  2. Key Laboratory for Pediatrics of Integrated Traditional and Western Medicine, Liaocheng People’s Hospital, Liaocheng, 252000, Shandong, People’s Republic of China

    Jing Wang

  3. Central Laboratory, Liaocheng People’s Hospital, Liaocheng, 252000, Shandong, People’s Republic of China

    Wenqiang Tang

  4. Department of Hematology, Liaocheng People’s Hospital, Liaocheng, 252000, Shandong, People’s Republic of China

    Xiaole Zhang

Authors
  1. Tianying Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenqiang Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongliang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaole Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dawei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TR, JW, WT, XZ, and DY made substantial contributions to conception and design. TR, JW, WT, DC, and SW contributed to acquisition of data, analysis and interpretation of data. All authors drafted the manuscript. TR, JW, XZ, and DY revised it critically for important intellectual content. All authors have given final approval of the version to be published.

Corresponding authors

Correspondence to Xiaole Zhang or Dawei Yang.

Ethics declarations

Conflict of interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The experimental procedures of the present study have been approved by the Ethics Committee of Liaocheng People’s Hospital (Number: LY2017026).

Consent to participate

All patients signed the written informed consent.

Consent for publication

All patients signed the written informed consent for publication.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ren, T., Wang, J., Tang, W. et al. ARID1A has prognostic value in acute myeloid leukemia and promotes cell proliferation via TGF-β1/SMAD3 signaling. Clin Exp Med 23, 777–785 (2023). https://doi.org/10.1007/s10238-022-00863-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-022-00863-8

Keywords

Search

Navigation