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.

  • Original Article
  • Published:

Transcriptional Control and Signal Transduction

Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia

Leukemia volume 28, pages 349–361 (2014)Cite this article

Subjects

Abstract

Long-range chromatin interactions control metazoan gene transcription. However, the involvement of intra- and interchromosomal interactions in development and oncogenesis remains unclear. TAL1/SCL is a critical transcription factor required for the development of all hematopoietic lineages; yet, aberrant TAL1 transcription often occurs in T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that oncogenic TAL1 expression is regulated by different intra- and interchromosomal loops in normal hematopoietic and leukemic cells, respectively. These intra- and interchromosomal loops alter the cell-type-specific enhancers that interact with the TAL1 promoter. We show that human SET1 (hSET1)-mediated H3K4 methylations promote a long-range chromatin loop, which brings the +51 enhancer in close proximity to TAL1 promoter 1 in erythroid cells. The CCCTC-binding factor (CTCF) facilitates this long-range enhancer/promoter interaction of the TAL1 locus in erythroid cells while blocking the same enhancer/promoter interaction of the TAL1 locus in human T-cell leukemia. In human T-ALL, a T-cell-specific transcription factor c-Maf-mediated interchromosomal interaction brings the TAL1 promoter into close proximity with a T-cell-specific regulatory element located on chromosome 16, activating aberrant TAL1 oncogene expression. Thus, our study reveals a novel molecular mechanism involving changes in three-dimensional chromatin interactions that activate the TAL1 oncogene in human T-cell leukemia.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Aplan PD, Begley CG, Bertness V, Nussmeier M, Ezquerra A, Coligan J et al. The SCL gene is formed from a transcriptionally complex locus. Mol Cell Biol 1990; 10: 6426–6435.

    Article  CAS  Google Scholar 

  2. 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: 2031–2035.

    Article  CAS  Google Scholar 

  3. Chen Q, Yang CY, Tsan JT, Xia Y, Ragab AH, Peiper SC et al. Coding sequences of the tal-1 gene are disrupted by chromosome translocation in human T cell leukemia. J Exp Med 1990; 172: 1403–1408.

    Article  CAS  Google Scholar 

  4. Finger LR, Kagan J, Christopher G, Kurtzberg J, Hershfield MS, Nowell PC et al. Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma. Proc Natl Acad Sci USA 1989; 86: 5039–5043.

    Article  CAS  Google Scholar 

  5. Robb L, Lyons I, Li R, Hartley L, Kontgen F, Harvey RP et al. Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc Natl Acad Sci USA 1995; 92: 7075–7079.

    Article  CAS  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: 432–434.

    Article  CAS  Google Scholar 

  7. Robb L, Elwood NJ, Elefanty AG, Kontgen F, Li R, Barnett LD et al. The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. Embo J 1996; 15: 4123–4129.

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

  9. Hu X, Ybarra R, Qiu Y, Bungert J, Huang S . Transcriptional regulation by TAL1: a link between epigenetic modifications and erythropoiesis. Epigenetics 2009; 4: 357–361.

    Article  CAS  Google Scholar 

  10. Cardoso BA, de Almeida SF, Laranjeira AB, Carmo-Fonseca M, Yunes JA, Coffer PJ et al. TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells. Leukemia 2011; 25: 1578–1586.

    Article  CAS  Google Scholar 

  11. Hu G, Schones DE, Cui K, Ybarra R, Northrup D, Tang Q et al. Regulation of nucleosome landscape and transcription factor targeting at tissue-specific enhancers by BRG1. Genome Res 2011; 21: 1650–1658.

    Article  CAS  Google Scholar 

  12. Dhami P, Bruce AW, Jim JH, Dillon SC, Hall A, Cooper JL et al. Genomic approaches uncover increasing complexities in the regulatory landscape at the human SCL (TAL1) locus. PLoS ONE 2010; 5: e9059.

    Article  Google Scholar 

  13. Ogilvy S, Ferreira R, Piltz SG, Bowen JM, Gottgens B, Green AR . The SCL +40 enhancer targets the midbrain together with primitive and definitive hematopoiesis and is regulated by SCL and GATA proteins. Mol Cell Biol 2007; 27: 7206–7219.

    Article  CAS  Google Scholar 

  14. Delabesse E, Ogilvy S, Chapman MA, Piltz SG, Gottgens B, Green AR . Transcriptional regulation of the SCL locus: identification of an enhancer that targets the primitive erythroid lineage in vivo. Mol Cell Biol 2005; 25: 5215–5225.

    Article  CAS  Google Scholar 

  15. Gottgens B, Barton LM, Chapman MA, Sinclair AM, Knudsen B, Grafham D et al. Transcriptional regulation of the stem cell leukemia gene (SCL)—comparative analysis of five vertebrate SCL loci. Genome Res 2002; 12: 749–759.

    Article  CAS  Google Scholar 

  16. Gottgens B, Barton LM, Gilbert JG, Bench AJ, Sanchez MJ, Bahn S et al. Analysis of vertebrate SCL loci identifies conserved enhancers. Nat Biotechnol 2000; 18: 181–186.

    Article  CAS  Google Scholar 

  17. Follows GA, Dhami P, Gottgens B, Bruce AW, Campbell PJ, Dillon SC et al. Identifying gene regulatory elements by genomic microarray mapping of DNaseI hypersensitive sites. Genome Res 2006; 16: 1310–1319.

    Article  CAS  Google Scholar 

  18. Silberstein L, Sanchez MJ, Socolovsky M, Liu Y, Hoffman G, Kinston S et al. Transgenic analysis of the stem cell leukemia +19 stem cell enhancer in adult and embryonic hematopoietic and endothelial cells. Stem Cells 2005; 23: 1378–1388.

    Article  CAS  Google Scholar 

  19. Gottgens B, Gilbert JG, Barton LM, Grafham D, Rogers J, Bentley DR et al. Long-range comparison of human and mouse SCL loci: localized regions of sensitivity to restriction endonucleases correspond precisely with peaks of conserved noncoding sequences. Genome Res 2001; 11: 87–97.

    Article  CAS  Google Scholar 

  20. Bockamp EO, McLaughlin F, Murrell AM, Gottgens B, Robb L, Begley CG et al. Lineage-restricted regulation of the murine SCL/TAL-1 promoter. Blood 1995; 86: 1502–1514.

    CAS  Google Scholar 

  21. Gottgens B, Broccardo C, Sanchez MJ, Deveaux S, Murphy G, Gothert JR et al. The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5' bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol 2004; 24: 1870–1883.

    Article  Google Scholar 

  22. Brown L, Cheng JT, Chen Q, Siciliano MJ, Crist W, Buchanan G et al. Site-specific recombination of the tal-1 gene is a common occurrence in human T cell leukemia. Embo J 1990; 9: 3343–3351.

    Article  CAS  Google Scholar 

  23. Bash RO, Hall S, Timmons CF, Crist WM, Amylon M, Smith RG et al. Does activation of the TAL1 gene occur in a majority of patients with T-cell acute lymphoblastic leukemia? A pediatric oncology group study. Blood 1995; 86: 666–676.

    CAS  Google Scholar 

  24. Carroll AJ, Crist WM, Link MP, Amylon MD, Pullen DJ, Ragab AH et al. The t(1;14)(p34;q11) is nonrandom and restricted to T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 1990; 76: 1220–1224.

    CAS  Google Scholar 

  25. Condorelli GL, Facchiano F, Valtieri M, Proietti E, Vitelli L, Lulli V et al. T-cell-directed TAL-1 expression induces T-cell malignancies in transgenic mice. Cancer Res 1996; 56: 5113–5119.

    CAS  Google Scholar 

  26. Kelliher MA, Seldin DC, Leder P . Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha. Embo J 1996; 15: 5160–5166.

    Article  CAS  Google Scholar 

  27. Palii CG, Perez-Iratxeta C, Yao Z, Cao Y, Dai F, Davison J et al. Differential genomic targeting of the transcription factor TAL1 in alternate haematopoietic lineages. Embo J 2011; 30: 494–509.

    Article  CAS  Google Scholar 

  28. Hu X, Li X, Valverde K, Fu X, Noguchi C, Qiu Y et al. LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc Natl Acad Sci USA 2009; 106: 10141–10146.

    Article  CAS  Google Scholar 

  29. Li X, Wang S, Li Y, Deng C, Steiner LA, Xiao H et al. Chromatin boundaries require functional collaboration between the hSET1 and NURF complexes. Blood 2011; 118: 1386–1394.

    Article  CAS  Google Scholar 

  30. Huang S, Litt M, Felsenfeld G . Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications. Genes Dev 2005; 19: 1885–1893.

    Article  CAS  Google Scholar 

  31. Cui K, Zang C, Roh TY, Schones DE, Childs RW, Peng W et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 2009; 4: 80–93.

    Article  CAS  Google Scholar 

  32. Li X, Hu X, Patel B, Zhou Z, Liang S, Ybarra R et al. H4R3 methylation facilitates beta-globin transcription by regulating histone acetyltransferase binding and H3 acetylation. Blood 2010; 115: 2028–2037.

    Article  CAS  Google Scholar 

  33. Hagege H, Klous P, Braem C, Splinter E, Dekker J, Cathala G et al. Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nature protocols 2007; 2: 1722–1733.

    Article  CAS  Google Scholar 

  34. Abou El Hassan M, Bremner R . A rapid simple approach to quantify chromosome conformation capture. Nucleic Acids Res 2009; 37: e35.

    Article  CAS  Google Scholar 

  35. Gondor A, Rougier C, Ohlsson R . High-resolution circular chromosome conformation capture assay. Nat Protoc 2008; 3: 303–313.

    Article  Google Scholar 

  36. Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 2009; 459: 108–112.

    Article  CAS  Google Scholar 

  37. Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 2007; 39: 311–318.

    Article  CAS  Google Scholar 

  38. Li Y, Deng C, Hu X, Patel B, Fu X, Qiu Y et al. Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis. Oncogene 2012; 31: 5007–5018.

    Article  CAS  Google Scholar 

  39. Li G, Ruan X, Auerbach RK, Sandhu KS, Zheng M, Wang P et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 2012; 148: 84–98.

    Article  CAS  Google Scholar 

  40. Sanyal A, Lajoie BR, Jain G, Dekker J . The long-range interaction landscape of gene promoters. Nature 2012; 489: 109–113.

    Article  CAS  Google Scholar 

  41. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129: 823–837.

    Article  CAS  Google Scholar 

  42. Follows GA, Ferreira R, Janes ME, Spensberger D, Cambuli F, Chaney AF et al. Mapping and functional characterisation of a CTCF-dependent insulator element at the 3' border of the murine Scl transcriptional domain. PLoS ONE 2012; 7: e31484.

    Article  CAS  Google Scholar 

  43. Wallace JA, Felsenfeld G . We gather together: insulators and genome organization. Curr Opin Genet Dev 2007; 17: 400–407.

    Article  CAS  Google Scholar 

  44. Phillips JE, Corces VG . CTCF: master weaver of the genome. Cell 2009; 137: 1194–1211.

    Article  Google Scholar 

  45. Huang Y, Sitwala K, Bronstein J, Sanders D, Dandekar M, Collins C et al. Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood 2012; 119: 388–398.

    Article  CAS  Google Scholar 

  46. Kim JI, Ho IC, Grusby MJ, Glimcher LH . The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 1999; 10: 745–751.

    Article  CAS  Google Scholar 

  47. Cao S, Liu J, Song L, Ma X . The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol 2005; 174: 3484–3492.

    Article  CAS  Google Scholar 

  48. Murakami YI, Yatabe Y, Sakaguchi T, Sasaki E, Yamashita Y, Morito N et al. c-Maf expression in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2007; 31: 1695–1702.

    Article  Google Scholar 

  49. Morito N, Yoh K, Fujioka Y, Nakano T, Shimohata H, Hashimoto Y et al. Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human. Cancer Res 2006; 66: 812–819.

    Article  CAS  Google Scholar 

  50. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.

    Article  CAS  Google Scholar 

  51. Mitsiou DJ, Stunnenberg HG . p300 is involved in formation of the TBP-TFIIA-containing basal transcription complex, TAC. Embo J 2003; 22: 4501–4511.

    Article  CAS  Google Scholar 

  52. Bernard O, Azogui O, Lecointe N, Mugneret F, Berger R, Larsen CJ et al. A third tal-1 promoter is specifically used in human T cell leukemias. J Exp Med 1992; 176: 919–925.

    Article  CAS  Google Scholar 

  53. Schubeler D, Francastel C, Cimbora DM, Reik A, Martin DI, Groudine M . Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human beta-globin locus. Genes Dev 2000; 14: 940–950.

    CAS  Google Scholar 

  54. Song SH, Hou C, Dean A . A positive role for NLI/Ldb1 in long-range beta-globin locus control region function. Mol Cell 2007; 28: 810–822.

    Article  CAS  Google Scholar 

  55. Vakoc CR, Letting DL, Gheldof N, Sawado T, Bender MA, Groudine M et al. Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. Mol Cell 2005; 17: 453–462.

    Article  CAS  Google Scholar 

  56. Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G . CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell 2004; 13: 291–298.

    Article  CAS  Google Scholar 

  57. Aplan PD, Raimondi SC, Kirsch IR . Disruption of the SCL gene by a t(1;3) translocation in a patient with T cell acute lymphoblastic leukemia. J Exp Med 1992; 176: 1303–1310.

    Article  CAS  Google Scholar 

  58. Breit TM, Mol EJ, Wolvers-Tettero IL, Ludwig WD, van Wering ER, van Dongen JJ . Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes. J Exp Med 1993; 177: 965–977.

    Article  CAS  Google Scholar 

  59. Aplan PD, Lombardi DP, Ginsberg AM, Cossman J, Bertness VL, Kirsch IR . Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity. Science 1990; 250: 1426–1429.

    Article  CAS  Google Scholar 

  60. Ong CT, Corces VG . Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 2011; 12: 283–293.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to members of the Huang laboratory for their suggestions and comments. We thank Drs Christopher Cogle and Zhixiong Xu for generously providing T-ALL samples and for their advice on the 4C assay. This work was supported by grants from the National Institute of Health (SH, R01HL090589, R01HL091929 and R01HL091929-01A1S1-the ARRA Administrative supplement; YQ, R01HL095674; BP, 5T32CA009126-35). KZ is supported by the Intramural Research programs, the National Heart Lung Blood Institute, and the National Institute of Health.

Author information

Author notes

  1. B Patel and Y Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA

    B Patel, Y Kang, M S J Riberio, C Deng, T Salz & S Huang

  2. College of Life Science, Jilin University, Changchun, China

    Y Kang & X Fu

  3. Center for System Biology, NHLBI, National Institute of Health, Bethesda, MD, USA

    K Cui & K Zhao

  4. Medical Education Center, Ball State University, Muncie, IN, USA

    M Litt & S Casada

  5. Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA

    Y Qiu

  6. Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL, USA

    Y Qiu & S Huang

Authors
  1. B Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Litt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M S J Riberio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Salz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Casada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. X Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Huang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patel, B., Kang, Y., Cui, K. et al. Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia. Leukemia 28, 349–361 (2014). https://doi.org/10.1038/leu.2013.158

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.158

Keywords

This article is cited by

Search

Advanced search

Quick links