SpringerLink
Log in

ACUTE LYMPHOBLASTIC LEUKEMIA

Oncogenic dependency on SWI/SNF chromatin remodeling factors in T-cell acute lymphoblastic leukemia

  • Article
  • Published:
Leukemia Submit manuscript

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy arising from immature thymocytes. Unlike well-known oncogenic transcription factors, such as NOTCH1 and MYC, the involvement of chromatin remodeling factors in T-ALL pathogenesis is poorly understood. Here, we provide compelling evidence on how SWI/SNF chromatin remodeling complex contributes to human T-ALL pathogenesis. Integrative analysis of transcriptomic and ATAC-Seq datasets revealed high expression of SMARCA4, one of the subunits of the SWI/SNF complex, in T-ALL patient samples and cell lines compared to normal T cells. Loss of SMARCA protein function resulted in apoptosis induction and growth inhibition in multiple T-ALL cell lines. ATAC-Seq analysis revealed a massive reduction in chromatin accessibility across the genome after the loss of SMARCA protein function. RUNX1 interacts with SMARCA4 protein and co-occupies the same genomic regions. Importantly, the NOTCH1-MYC pathway was primarily affected when SMARCA protein function was impaired, implicating SWI/SNF as a novel therapeutic target.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: SMARCA4 is required for T-ALL cell growth and survival.
Fig. 2: SMARCA4 protein levels are associated with ACBI-1 drug sensitivity.
Fig. 3: The NOTCH1-MYC pathway is the main target of SWI/SNF in T-ALL.
Fig. 4: Depletion of SWI/SNF results in a rapid loss of open chromatin regions.
Fig. 5: Interplays between oncogenic transcription factors and SWI/SNF.

Data availability

The publicly available datasets [19, 29, 39,40,41,42] and the self-generated datasets are listed in Supplementary Table S4.

References

  1. Aifantis I, Raetz E, Buonamici S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol. 2008;8:380–90.

    Article  CAS  PubMed  Google Scholar 

  2. Van Vlierberghe P, Ferrando A. The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest. 2012;122:3398–406.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Belver L, Ferrando A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer. 2016;16:494–507.

    Article  CAS  PubMed  Google Scholar 

  4. Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29:551–65.

    Article  PubMed  Google Scholar 

  5. Patel AA, Thomas J, Rojek AE, Stock W. Biology and treatment paradigms in T cell acute lymphoblastic leukemia in older adolescents and adults. Curr Treat Options Oncol. 2020;21:57.

    Article  PubMed  Google Scholar 

  6. Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol. 2005;23:6306–15.

    Article  CAS  PubMed  Google Scholar 

  7. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Weng AP, Ferrando AA, Lee W, Morris JPT, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269–71.

    Article  CAS  PubMed  Google Scholar 

  9. Tan SH, Bertulfo FC, Sanda T. Leukemia-initiating cells in T-cell acute lymphoblastic leukemia. Front Oncol. 2017;7:218.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Weng Y, Khatri B, Hong G, Wang F, Chen Z, Huang Q. Protective effect of interleukin-1beta on motor neurons after sciatic nerve injury in rats. J Huazhong Univ Sci Technol Med Sci. 2004;24:71–4.

    CAS  Google Scholar 

  11. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med. 2014;20:1130–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sanda T, Lawton LN, Barrasa MI, Fan ZP, Kohlhammer H, Gutierrez A, et al. Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia. Cancer Cell. 2012;22:209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liau WS, Tan SH, Ngoc PCT, Wang CQ, Tergaonkar V, Feng H, et al. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia. 2017;31:1798–807.

    Article  CAS  PubMed  Google Scholar 

  14. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  15. Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015;1:e1500447.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mittal P, Roberts CWM. The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020;17:435–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Clapier CR, Iwasa J, Cairns BR, Peterson CL. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol. 2017;18:407–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Heng TS, Painter MW, Immunological Genome Project C. The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol. 2008;9:1091–4.

    Article  CAS  PubMed  Google Scholar 

  19. Corces MR, Buenrostro JD, Wu B, Greenside PG, Chan SM, Koenig JL, et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat Genet. 2016;48:1193–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. DepMap, Broad. This DepMap release contains data from CRISPR knockout screens from project Achilles, as well as genomic characterization data from the CCLE project. For more information, please see README.txt. figshare. Dataset. 2023.

  21. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181–200.

    Article  PubMed  PubMed Central  Google Scholar 

  22. **ao L, Parolia A, Qiao Y, Bawa P, Eyunni S, Mannan R, et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature. 2022;601:434–9.

    Article  CAS  PubMed  Google Scholar 

  23. Draheim KM, Hermance N, Yang Y, Arous E, Calvo J, Kelliher MA. A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice. Oncogene. 2011;30:1252–60.

    Article  CAS  PubMed  Google Scholar 

  24. Papillon JPN, Nakajima K, Adair CD, Hempel J, Jouk AO, Karki RG, et al. Discovery of orally active inhibitors of brahma homolog (BRM)/SMARCA2 ATPase activity for the treatment of Brahma related gene 1 (BRG1)/SMARCA4-mutant cancers. J Med Chem. 2018;61:10155–72.

    Article  CAS  PubMed  Google Scholar 

  25. Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 2013;27:2648–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. O’Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007;204:1813–24.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 2008;118:3762–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schick S, Grosche S, Kohl KE, Drpic D, Jaeger MG, Marella NC, et al. Acute BAF perturbation causes immediate changes in chromatin accessibility. Nat Genet. 2021;53:269–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kloetgen A, Thandapani P, Ntziachristos P, Ghebrechristos Y, Nomikou S, Lazaris C, et al. Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia. Nat Genet. 2020;52:388–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O, Judde JG, et al. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol Cell. 2012;48:445–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45:592–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Choi A, Illendula A, Pulikkan JA, Roderick JE, Tesell J, Yu J, et al. RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood. 2017;130:1722–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schneider M, Radoux CJ, Hercules A, Ochoa D, Dunham I, Zalmas LP, et al. The PROTACtable genome. Nat Rev Drug Discov. 2021;20:789–97.

    Article  CAS  PubMed  Google Scholar 

  34. Zhao L, Zhao J, Zhong K, Tong A, Jia D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther. 2022;7:113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–73.

    Article  CAS  PubMed  Google Scholar 

  36. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mumbach MR, Rubin AJ, Flynn RA, Dai C, Khavari PA, Greenleaf WJ, et al. HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat Methods. 2016;13:919–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Buenrostro JD, Wu B, Chang HY, Greenleaf WJ. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr Protoc Mol Biol. 2015;109:21.9.1–9.9.

    Google Scholar 

  39. Abraham BJ, Hnisz D, Weintraub AS, Kwiatkowski N, Li CH, Li Z, et al. Small genomic insertions form enhancers that misregulate oncogenes. Nat Commun. 2017;8:14385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH roadmap epigenomics map** consortium. Nat Biotechnol. 2010;28:1045–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature. 2015;520:558–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014;511:616–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Springer Nature Author Services for editing the manuscript. We thank the members of the Sanda laboratory for discussions and critical reviews. This research is supported by the National Medical Research Council of the Singapore Ministry of Health (MOH-000208-00: TS; and MOH-001225-00: TS. AEJY); NCIS-N2CR Grant (TS, AEJY), the Singapore Ministry of Education (MOE-000061-00: TS); the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative; and the Japan Society for the Promotion of Science (18K19960: TS).

Author information

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of, Singapore, 117599, Singapore

    Hyoju Kim, Tze King Tan, Dean Zi Yang Lee, **ao Zi Huang, Jolynn Zu Lin Ong, Allen Eng Juh Yeoh, Takaomi Sanda & Shi Hao Tan

  2. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Michelle A. Kelliher

  3. Department of Pediatrics, National University of, Singapore, Singapore

    Allen Eng Juh Yeoh

  4. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore

    Takaomi Sanda

  5. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan

    Takaomi Sanda

Authors
  1. Hyoju Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tze King Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dean Zi Yang Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. **ao Zi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jolynn Zu Lin Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michelle A. Kelliher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Allen Eng Juh Yeoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takaomi Sanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shi Hao Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HK, DL, XZH, JZLO and SHT performed the experiments; TKT conducted the bioinformatics analyses; MAK provided mice; MAK, AEJY, TS and SHT supervised the study; and HK, SHT, and TS wrote the manuscript.

Corresponding author

Correspondence to Takaomi Sanda.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The animal protocols (protocol numbers: R20-0436, R20-1109, R22-0346) were approved by the Institutional Animal Care and Use Committee of the National University of Singapore.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, H., Tan, T.K., Lee, D.Z.Y. et al. Oncogenic dependency on SWI/SNF chromatin remodeling factors in T-cell acute lymphoblastic leukemia. Leukemia (2024). https://doi.org/10.1038/s41375-024-02331-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41375-024-02331-6

  • Springer Nature Limited

Search

Navigation