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 LYMPHOBLASTIC LEUKEMIA

TAL1 hijacks MYCN enhancer that induces MYCN expression and dependence on mevalonate pathway in T-cell acute lymphoblastic leukemia

Leukemia volume 37, pages 1969–1981 (2023)Cite this article

Subjects

A Correction to this article was published on 25 January 2024

This article has been updated

Abstract

A hallmark of T-cell acute lymphoblastic leukemia (T-ALL) is the dysregulated expression of oncogenic transcription factors (TFs), including TAL1, NOTCH1 and MYC. Rewiring of the transcriptional program disrupts the tightly controlled spatiotemporal expression of downstream target genes, thereby contributing to leukemogenesis. In this study, we first identify an evolutionarily conserved enhancer element controlling the MYCN oncogene (named enhMYCN) that is aberrantly activated by the TAL1 complex in T-ALL cells. TAL1-positive T-ALL cells are highly dependent on MYCN expression for their maintenance in vitro and in xenograft models. Interestingly, MYCN drives the expression of multiple genes involved in the mevalonate pathway, and T-ALL cells are sensitive to inhibition of HMG-CoA reductase (HMGCR), a rate-limiting enzyme of this pathway. Importantly, MYC and MYCN regulate the same targets and compensate for each other. Thus, MYCN-positive T-ALL cells display a dual dependence on the TAL1-MYCN and NOTCH1-MYC pathways. Together, our results demonstrate that enhMYCN-mediated MYCN expression is required for human T-ALL cells and implicate the TAL1-MYCN-HMGCR axis as a potential therapeutic target in T-ALL.

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: Opening of a conserved MYCN enhancer element bound by the TAL1 transcriptional complex is correlated with MYCN expression in T-ALL.
Fig. 2: enhMYCN is aberrantly activated by the TAL1 transcriptional complex to initiate MYCN expression in T-ALL cells.
Fig. 3: Both the enhMYCN element and MYCN expression are essential to maintain the survival of T-ALL cells.
Fig. 4: MYCN regulates cholesterol synthesis in T-ALL cells via direct activation of genes involved in the mevalonate pathway.
Fig. 5: The mevalonate pathway is essential for T-ALL cell survival.
Fig. 6: Overlap of genome-wide binding and functional cooperation between MYC and MYCN.

Similar content being viewed by others

Data availability

All data are available from the authors upon reasonable request. RNA-seq, ChIP-seq, CUT&RUN, ATAC-seq and Hi-ChIP data have been deposited. ATAC-Seq datasets of human hematopoietic cells were obtained from GSE74912. ChIP-Seq datasets of human CD34+ cells were obtained from BloodChIP [48]. ChIP-Seq datasets in Jurkat were obtained from: GSE29181, GSE68976, GSE59657, GSE97514 and GSM 1296384. Gene expression datasets for primary T-ALL samples reported by the TARGET project [2] were downloaded from dbGAP database (phs000218). Gene expression data of other primary T-ALL samples were obtained from: GSE26713 and GSE42328. All sequencing dataset have been deposited in the Gene Expression Omnibus database under the accession number GSE231965.

Change history

References

  1. 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 

  2. 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 

  3. Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood. 2017;129:1113–23.

    Article  CAS  PubMed  Google Scholar 

  4. Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science. 2014;346:1373–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Begley CG, Aplan PD, Davey MP, Nakahara K, Tchorz K, Kurtzberg J, et al. Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript. Proc Natl Acad Sci USA. 1989;86:2031–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shivdasani RA, Mayer EL, Orkin SH. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995;373:432–4.

    Article  CAS  PubMed  Google Scholar 

  7. Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell. 1996;86:47–57.

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Sanda T, Leong WZ. TAL1 as a master oncogenic transcription factor in T-cell acute lymphoblastic leukemia. Exp Hematol. 2017;53:7–15.

    Article  CAS  PubMed  Google Scholar 

  10. Wilson NK, Foster SD, Wang X, Knezevic K, Schutte J, Kaimakis P, et al. Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell. 2010;7:532–44.

    Article  CAS  PubMed  Google Scholar 

  11. Tan SH, Leong WZ, Ngoc PCT, Tan TK, Bertulfo FC, Lim MC, et al. The enhancer RNA ARIEL activates the oncogenic transcriptional program in T-cell acute lymphoblastic leukemia. Blood. 2019;134:239–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tan SH, Yam AW, Lawton LN, Wong RW, Young RA, Look AT, et al. TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia. 2016;30:959–62.

    Article  CAS  PubMed  Google Scholar 

  13. Leong WZ, Tan SH, Ngoc PCT, Amanda S, Yam AWY, Liau WS, et al. ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis. Genes Dev. 2017;31:2343–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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 

  15. Tremblay M, Tremblay CS, Herblot S, Aplan PD, Hébert J, Perreault C, et al. Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes. Genes Dev. 2010;24:1093–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. O’Neil J, Shank J, Cusson N, Murre C, Kelliher M. TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell. 2004;5:587–96.

    Article  PubMed  Google Scholar 

  17. Tatarek J, Cullion K, Ashworth T, Gerstein R, Aster JC, Kelliher MA. Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood. 2011;118:1579–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 

  19. Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA. 2006;103:18261–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol. 2006;26:8022–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006;20:2096–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mansour MR, Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD, et al. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med. 2013;210:1545–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ruiz-Pérez MV, Henley AB, Arsenian-Henriksson M. The MYCN protein in health and disease. Genes. 2017;8:113.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rickman DS, Schulte JH, Eilers M. The expanding world of N-MYC-driven tumors. Cancer Discov. 2018;8:150–63.

    Article  CAS  PubMed  Google Scholar 

  26. Astolfi A, Vendemini F, Urbini M, Melchionda F, Masetti R, Franzoni M, et al. MYCN is a novel oncogenic target in pediatric T-cell acute lymphoblastic leukemia. Oncotarget. 2014;5:120–30.

    Article  PubMed  Google Scholar 

  27. Ngoc PCT, Tan SH, Tan TK, Chan MM, Li Z, Yeoh AEJ, et al. Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia. 2018;32:2138–51.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Malynn BA, de Alboran IM, O’Hagan RC, Bronson R, Davidson L, DePinho RA, et al. N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. Genes Dev. 2000;14:1390–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dubois NC, Adolphe C, Ehninger A, Wang RA, Robertson EJ, Trumpp A. Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function. Development. 2008;135:2455–65.

    Article  CAS  PubMed  Google Scholar 

  30. Laurenti E, Varnum-Finney B, Wilson A, Ferrero I, Blanco-Bose WE, Ehninger A, et al. Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell. 2008;3:611–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M, et al. ETV6 mutations in early immature human T cell leukemias. J Exp Med. 2011;208:2571–9.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Booth CAG, Barkas N, Neo WH, Boukarabila H, Soilleux EJ, Giotopoulos G, et al. Ezh2 and Runx1 mutations collaborate to initiate lympho-myeloid leukemia in early thymic progenitors. Cancer Cell. 2018;33:274–91.e8.

    Article  CAS  PubMed  Google Scholar 

  33. Thakore PI, D’Ippolito AM, Song L, Safi A, Shivakumar NK, Kabadi AM, et al. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods. 2015;12:1143–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Leon TE, Rapoz-D’Silva T, Bertoli C, Rahman S, Magnussen M, Philip B, et al. EZH2-deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress. Cancer Discov. 2020;10:998–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kee BL. E and ID proteins branch out. Nat Rev Immunol. 2009;9:175–84.

    Article  CAS  PubMed  Google Scholar 

  36. Rothenberg EV, Moore JE, Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol. 2008;8:9–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zeid R, Lawlor MA, Poon E, Reyes JM, Fulciniti M, Lopez MA, et al. Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma. Nat Genet. 2018;50:515–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vanden Bempt M, Debackere K, Demeyer S, Van Thillo Q, Meeuws N, Fernandez CP, et al. Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T cell lymphoma. Blood. 2022;140:2463–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shen L, O’Shea JM, Kaadige MR, Cunha S, Wilde BR, Cohen AL, et al. Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc Natl Acad Sci USA. 2015;112:5425–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, et al. Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell. 2015;27:271–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. King B, Boccalatte F, Moran-Crusio K, Wolf E, Wang J, Kayembe C, et al. The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells. Nat Immunol. 2016;17:1312–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13:1203–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rao SS, O’Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, et al. Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res. 2009;69:3060–8.

    Article  CAS  PubMed  Google Scholar 

  44. Lacher SM, Bruttger J, Kalt B, Berthelet J, Rajalingam K, Wortge S, et al. HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival. Cell Death Dis. 2017;8:e2824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 2016;16:718–31.

    Article  CAS  PubMed  Google Scholar 

  46. Juarez D, Fruman DA. Targeting the mevalonate pathway in cancer. Trends Cancer. 2021;7:525–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rashkovan M, Albero R, Gianni F, Perez-Duran P, Miller HI, Mackey AL, et al. Intracellular cholesterol pools regulate oncogenic signaling and epigenetic circuitries in early T-cell precursor acute lymphoblastic leukemia. Cancer Discov. 2022;12:856–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chacon D, Beck D, Perera D, Wong JW, Pimanda JE. BloodChIP: a database of comparative genome-wide transcription factor binding profiles in human blood cells. Nucleic Acids Res. 2014;42:D172–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank 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-000208-01: TS; MOH-000228-00: SHT), the Singapore Ministry of Education (MOE-000061-01: TS), and the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative (TS). The RNA-seq result here is based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) (https://ocg.cancer.gov/programs/target) initiative, phs000218.

Author information

Authors and Affiliations

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

    Shi Hao Tan, Tze King Tan, Rui Yokomori, Minghui Liao, Xiao Zi Huang, Allen Eng Juh Yeoh & Takaomi Sanda

  2. Department of Paediatrics, National University of Singapore, Singapore, 119228, Singapore

    Allen Eng Juh Yeoh

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

    Takaomi Sanda

Authors
  1. Shi Hao Tan
    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. Rui Yokomori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Minghui Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao Zi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Allen Eng Juh Yeoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takaomi Sanda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SHT, MHL and XZH performed the experiments; TKT and RY conducted the bioinformatics analyses; AEJY, and TS supervised the study; and SHT and TS wrote the manuscript.

Corresponding authors

Correspondence to Allen Eng Juh Yeoh or Takaomi Sanda.

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

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

Tan, S.H., Tan, T.K., Yokomori, R. et al. TAL1 hijacks MYCN enhancer that induces MYCN expression and dependence on mevalonate pathway in T-cell acute lymphoblastic leukemia. Leukemia 37, 1969–1981 (2023). https://doi.org/10.1038/s41375-023-01993-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-023-01993-y

Search

Advanced search

Quick links