Acute lymphoblastic leukemia

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

Abstract

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.

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Acknowledgements

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 (2020). https://doi.org/10.1038/s41375-020-0864-3

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