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Acute lymphoblastic leukemia

TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition


T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by skewed epigenetic patterns, raising the possibility of therapeutically targeting epigenetic factors in this disease. Here we report that among different cancer types, epigenetic factor TET1 is highly expressed in T-ALL and is crucial for human T-ALL cell growth in vivo. Knockout of TET1 in mice and knockdown in human T cell did not perturb normal T-cell proliferation, indicating that TET1 expression is dispensable for normal T-cell growth. The promotion of leukemic growth by TET1 was dependent on its catalytic property to maintain global 5-hydroxymethylcytosine (5hmC) marks, thereby regulate cell cycle, DNA repair genes, and T-ALL associated oncogenes. Furthermore, overexpression of the Tet1-catalytic domain was sufficient to augment global 5hmC levels and leukemic growth of T-ALL cells in vivo. We demonstrate that PARP enzymes, which are highly expressed in T-ALL patients, participate in establishing H3K4me3 marks at the TET1 promoter and that PARP1 interacts with the TET1 protein. Importantly, the growth related role of TET1 in T-ALL could be antagonized by the clinically approved PARP inhibitor Olaparib, which abrogated TET1 expression, induced loss of 5hmC marks, and antagonized leukemic growth of T-ALL cells, opening a therapeutic avenue for this disease.

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Fig. 1: TET1 is highly expressed in T-ALL patients.
Fig. 2: TET1 is required for leukemic growth for human T-ALL.
Fig. 3: The enzymatic activity of TET1 is required for sustenance of T-ALL cells.
Fig. 4: TET1 regulates 5hmC marks in T-ALL cells.
Fig. 5: High TET1 expression protects T-ALL cells from DNA damage, accompanied by expression of cell cycle and DNA repair pathways.
Fig. 6: Enzymatic activity of PARPs regulates TET1 mRNA expression and protein stability in T-ALL cells.
Fig. 7: Olaparib treatment antagonizes TET1 expression and abrogates T-ALL cell growth in vitro and in vivo.


  1. 1.

    Bedford MT, van Helden PD. Hypomethylation of DNA in pathological conditions of the human prostate. Cancer Res. 1987;47:5274–6.

    CAS  PubMed  Google Scholar 

  2. 2.

    Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC, et al. Genome-wide hypomethylation in hepatocellular carcinogenesis. Cancer Res. 2001;61:4238–43.

    CAS  PubMed  Google Scholar 

  3. 3.

    Kim YI, Giuliano A, Hatch KD, Schneider A, Nour MA, Dallal GE, et al. Global DNA hypomethylation increases progressively in cervical dysplasia and carcinoma. Cancer. 1994;74:893–9.

    CAS  PubMed  Google Scholar 

  4. 4.

    Perez RF, Tejedor JR, Bayon GF, Fernandez AF, Fraga MF. Distinct chromatin signatures of DNA hypomethylation in aging and cancer. Aging Cell. 2018;17:e12744.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Zelic R, Fiano V, Grasso C, Zugna D, Pettersson A, Gillio-Tos A, et al. Global DNA hypomethylation in prostate cancer development and progression: a systematic review. Prostate Cancer Prostatic Dis. 2015;18:1–12.

    CAS  PubMed  Google Scholar 

  6. 6.

    Wahlfors J, Hiltunen H, Heinonen K, Hamalainen E, Alhonen L, Janne J. Genomic hypomethylation in human chronic lymphocytic leukemia. Blood. 1992;80:2074–80.

    CAS  PubMed  Google Scholar 

  7. 7.

    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333:1300–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Wu H, D’Alessio AC, Ito S, Wang Z, Cui K, Zhao K, et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 2011;25:679–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell. 2011;42:451–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Yang J, Guo R, Wang H, Ye X, Zhou Z, Dan J, et al. Tet enzymes regulate telomere maintenance and chromosomal stability of mouse ESCs. Cell Rep. 2016;15:1809–21.

    CAS  PubMed  Google Scholar 

  13. 13.

    Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20:11–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    An J, Gonzalez-Avalos E, Chawla A, Jeong M, Lopez-Moyado IF, Li W, et al. Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun. 2015;6:10071.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Weber AR, Krawczyk C, Robertson AB, Kusnierczyk A, Vagbo CB, Schuermann D, et al. Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism. Nat Commun. 2016;7:10806.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Neri F, Dettori D, Incarnato D, Krepelova A, Rapelli S, Maldotti M, et al. TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene. 2015;34:4168–76.

    CAS  PubMed  Google Scholar 

  17. 17.

    Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30:733–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118:4509–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zhao Z, Chen L, Dawlaty MM, Pan F, Weeks O, Zhou Y, et al. Combined Loss of Tet1 and Tet2 promotes B Cell, but not myeloid malignancies, in mice. Cell Rep. 2015;13:1692–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Cimmino L, Dawlaty MM, Ndiaye-Lobry D, Yap YS, Bakogianni S, Yu Y, et al. TET1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol. 2015;16:653–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kafer GR, Li X, Horii T, Suetake I, Tajima S, Hatada I, et al. 5-Hydroxymethylcytosine marks sites of DNA damage and promotes genome stability. Cell Rep. 2016;14:1283–92.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wang J, Li F, Ma Z, Yu M, Guo Q, Huang J, et al. High expression of TET1 predicts poor survival in cytogenetically normal acute myeloid leukemia from two cohorts. EBioMedicine. 2018;28:90–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep. 2013;3:291–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Wu MZ, Chen SF, Nieh S, Benner C, Ger LP, Jan CI, et al. Hypoxia drives breast tumor malignancy through a TET-TNFalpha-p38-MAPK signaling axis. Cancer Res. 2015;75:3912–24.

    CAS  PubMed  Google Scholar 

  25. 25.

    Yokoyama S, Higashi M, Tsutsumida H, Wakimoto J, Hamada T, Wiest E, et al. TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. Genes Cancer. 2017;8:517–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Huang H, Jiang X, Li Z, Li Y, Song CX, He C, et al. TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc Natl Acad Sci USA. 2013;110:11994–9.

    CAS  PubMed  Google Scholar 

  27. 27.

    Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia. 2003;17:637–41.

    CAS  PubMed  Google Scholar 

  28. 28.

    Jiang X, Hu C, Ferchen K, Nie J, Cui X, Chen CH, et al. Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun. 2017;8:2099.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Peirs S, Van der Meulen J, Van de Walle I, Taghon T, Speleman F, Poppe B, et al. Epigenetics in T-cell acute lymphoblastic leukemia. Immunol Rev. 2015;263:50–67.

    CAS  PubMed  Google Scholar 

  31. 31.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Vitale A, Guarini A, Ariola C, Mancini M, Mecucci C, Cuneo A, et al. Adult T-cell acute lymphoblastic leukemia: biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol. Blood. 2006;107:473–9.

    CAS  PubMed  Google Scholar 

  33. 33.

    Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet. 2014;46:364–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol. 2010;28:2529–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Poole CJ, Lodh A, Choi JH, van Riggelen J. MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL. Epigenetics Chromatin. 2019;12:41.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW, et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell. 2011;9:166–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Meyer LH, Eckhoff SM, Queudeville M, Kraus JM, Giordan M, Stursberg J, et al. Early relapse in ALL is identified by time to leukemia in NOD/SCID mice and is characterized by a gene signature involving survival pathways. Cancer Cell. 2011;19:206–17.

    CAS  PubMed  Google Scholar 

  39. 39.

    Hollingshead MG, Stockwin LH, Alcoser SY, Newton DL, Orsburn BC, Bonomi CA, et al. Gene expression profiling of 49 human tumor xenografts from in vitro culture through multiple in vivo passages-strategies for data mining in support of therapeutic studies. BMC Genom. 2014;15:393.

    Google Scholar 

  40. 40.

    Verma N, Pan H, Dore LC, Shukla A, Li QV, Pelham-Webb B, et al. TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells. Nat Genet. 2018;50:83–95.

    CAS  PubMed  Google Scholar 

  41. 41.

    Nestor CE, Lentini A, Hagg Nilsson C, Gawel DR, Gustafsson M, Mattson L, et al. 5-Hydroxymethylcytosine remodeling precedes lineage specification during differentiation of human CD4(+) T cells. Cell Rep. 2016;16:559–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Giambra V, Jenkins CE, Lam SH, Hoofd C, Belmonte M, Wang X, et al. Leukemia stem cells in T-ALL require active Hif1alpha and Wnt signaling. Blood. 2015;125:3917–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Evangelisti C, Ricci F, Tazzari P, Tabellini G, Battistelli M, Falcieri E, et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia. 2011;25:781–91.

    CAS  PubMed  Google Scholar 

  44. 44.

    Ciccarone F, Valentini E, Bacalini MG, Zampieri M, Calabrese R, Guastafierro T, et al. Poly(ADP-ribosyl)ation is involved in the epigenetic control of TET1 gene transcription. Oncotarget. 2014;5:10356–67.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Turgeon MO, Perry NJS, Poulogiannis G. DNA damage, repair, and cancer metabolism. Front Oncol. 2018;8:15.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Torgovnick A, Schumacher B. DNA repair mechanisms in cancer development and therapy. Front Genet. 2015;6:157.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Redon CE, Dickey JS, Bonner WM, Sedelnikova OA. gamma-H2AX as a biomarker of DNA damage induced by ionizing radiation in human peripheral blood lymphocytes and artificial skin. Adv Space Res. 2009;43:1171–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Banath JP, Macphail SH, Olive PL. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res. 2004;64:7144–9.

    CAS  PubMed  Google Scholar 

  49. 49.

    Jiang D, Wei S, Chen F, Zhang Y, Li J. TET3-mediated DNA oxidation promotes ATR-dependent DNA damage response. EMBO Rep. 2017;18:781–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Ciccarone F, Valentini E, Zampieri M, Caiafa P. 5mC-hydroxylase activity is influenced by the PARylation of TET1 enzyme. Oncotarget. 2015;6:24333–47.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Coulter JB, Lopez-Bertoni H, Kuhns KJ, Lee RS, Laterra J, Bressler JP. TET1 deficiency attenuates the DNA damage response and promotes resistance to DNA damaging agents. Epigenetics. 2017;12:854–64.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Zhong J, Li X, Cai W, Wang Y, Dong S, Yang J, et al. TET1 modulates H4K16 acetylation by controlling auto-acetylation of hMOF to affect gene regulation and DNA repair function. Nucleic Acids Res. 2017;45:672–84.

    CAS  PubMed  Google Scholar 

  54. 54.

    Tsagaratou A, Gonzalez-Avalos E, Rautio S, Scott-Browne JP, Togher S, Pastor WA, et al. TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. Nat Immunol. 2017;18:45–53.

    CAS  PubMed  Google Scholar 

  55. 55.

    Tsagaratou A, Lio CJ, Yue X, Rao A. TET methylcytosine oxidases in T cell and B cell development and function. Front Immunol. 2017;8:220.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, et al. Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016;213:377–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Roper SJ, Chrysanthou S, Senner CE, Sienerth A, Gnan S, Murray A, et al. ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells. Nucleic Acids Res. 2014;42:8914–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Parvin S, Ramirez-Labrada A, Aumann S, Lu X, Weich N, Santiago G, et al. LMO2 confers synthetic lethality to PARP inhibition in DLBCL. Cancer Cell. 2019;36:237–49 e236.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Nile DL, Rae C, Hyndman IJ, Gaze MN, Mairs RJ. An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma. BMC Cancer. 2016;16:621.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sanmartin E, Munoz L, Piqueras M, Sirerol JA, Berlanga P, Canete A, et al. Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition. Clin Cancer Res. 2017;23:6875–87.

    CAS  PubMed  Google Scholar 

  61. 61.

    Jiang Y, Dai H, Li Y, Yin J, Guo S, Lin SY, et al. PARP inhibitors synergize with gemcitabine by potentiating DNA damage in non-small-cell lung cancer. Int J Cancer. 2019;144:1092–103.

    CAS  PubMed  Google Scholar 

  62. 62.

    Pietanza MC, Waqar SN, Krug LM, Dowlati A, Hann CL, Chiappori A, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol. 2018;36:2386–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Colicchia V, Petroni M, Guarguaglini G, Sardina F, Sahun-Roncero M, Carbonari M, et al. PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma. Oncogene. 2017;36:4682–91.

    CAS  PubMed  Google Scholar 

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The authors would like to thank all members of the animal facility of the University of Ulm, Germany, for breeding and maintenance of the animals. The work was supported by a grant received by VPSR from the Ministry of Science, Research and the Art (MWK), Baden-Württemberg, Germany (Junior-professor Program, D.4268), and Baustein program 3.2, University of Ulm, Germany. FC is supported by a fellowship from the Italian Foundation for Cancer Research (AIRC). TH is supported by a Physician Scientists Grant from the Helmholtz Zentrum München. CB and MF-B were funded by grants from the DFG (SFB 1074 project A4 to CB and A6 to MF-B). Furthermore, we thank Medhanie A. Mulaw for his advice, participation in fruitful discussions, and helping in analysis of RNA-seq data. We would also like to thank Dr Dinesh Adhikary and Prof. Joseph Mautner for their support with Tcell assays.

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VPSR designed the project. SB, DD, AJP, EF, and FC performed experiments and SB, GtK, CBo, MF-B, CB, and VPSR analyzed the data. AS, SB, and VPSR performed the RNA-seq and ChIP-seq data analysis and FM and TH performed the microarray analysis. LQ-F and IG-M performed histopathology. CB, L-HM, K-MD, PC, IJ, TH, KD, and HD contributed research material. SB, CBo, GtK, L-HM, TH, VPSR, and CB contributed to interpretation of patient data. SB, CB, and VPSR wrote the manuscript.

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Correspondence to Christian Buske or Vijay P. S. Rawat.

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Bamezai, S., Demir, D., Pulikkottil, A.J. et al. TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition. Leukemia 35, 389–403 (2021).

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