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Transcriptional control and signal transduction, cell cycle

Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia

Leukemia volume 31, pages 1798–1807 (2017)Cite this article

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Abstract

The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the GIMAP locus, which resides within an insulated chromosomal locus in T-ALL cells. The GIMAP genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The GIMAP enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukemogenesis.

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Acknowledgements

We thank Rick Young, Lee Lawton and members of the Sanda laboratory for their discussions and critical reviews. We thank Wei Zhong Leong and Stella Amanda for their help with the zebrafish experiments. We are grateful to the NUS zebrafish facility for zebrafish analyses. This research is supported by the National Research Foundation, Prime Minister’s Office, Singapore, under its Competitive Research Programme (award no. NRF-NRFF2013-02), National Medical Research Council, the Singapore Ministry of Health (NMRC/CIRG/1443/2016), and the US National Cancer Institute (1K99CA157951). The research is also supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.

Author contributions

W-SL, SHT and TS performed the experiments; CQW, ZG and MO provided materials; W-SL, PCTN and TS analyzed the results; VT, MO and ATL supervised this study; and W-SL and TS designed the research and wrote the paper.

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Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore

    W S Liau, S H Tan, P C T Ngoc, C Q Wang, M Osato & T Sanda

  2. Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore

    C Q Wang & V Tergaonkar

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

    V Tergaonkar

  4. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia

    V Tergaonkar

  5. Department of Pharmacology and Experimental Therapeutics, Cancer Research Center, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA

    H Feng

  6. Department of Biological Sciences, National University of Singapore, Singapore, Singapore

    Z Gong

  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A T Look

  8. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA

    A T Look

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

    T Sanda

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  1. W S Liau
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Correspondence to T Sanda.

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Liau, W., Tan, S., Ngoc, P. et al. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia 31, 1798–1807 (2017). https://doi.org/10.1038/leu.2016.392

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