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Animal models

A novel TLX1-driven T-ALL zebrafish model: comparative genomic analysis with other leukemia models

Leukemia volume 34, pages 3398–3403 (2020)Cite this article

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Zebrafish (Danio rerio) has become a well-established and powerful in vivo model to study the molecular basis of T-cell acute lymphoblastic leukemia (T-ALL) [1]. Langenau et al. [2] were the first to generate a cancer model using transgenesis. Expression of the mouse Myc oncogene under the D. rerio lymphoblast-specific rag2 promoter resulted in rapid onset of leukemia [2]. However, since the development of this Myc model, the number of other oncogene-driven T-ALL models in zebrafish has remained limited.

The TLX1-driven T-ALL subtype encompasses 5–10% of pediatric and 30% of adult T-ALL cases, and is caused by a translocation that juxtaposes the TLX1 transcription factor near the T-cell receptor α or β enhancer region [3]. TLX1 acts as an oncogene in T-ALL, mainly by binding DNA regulatory regions to repress a network of T-ALL tumor suppressor genes including BCL11B, RUNX1, WT1, TET1, EZH2, FBXW7, PTEN, PTPN2 and mitotic checkpoint genes, leading to genomic instability and aneuploidy [4, 5]. Notably, 43.5% of TLX1/3-positive T-ALL harbor mutations in PHF6 [6] when compared to 9.5% in TLX1/3-negative cases [6], suggesting a functional cooperation between these genetic perturbations might drive leukemogenesis. PHF6 is amongst the most frequently affected genes in T-ALL due to loss-of-function mutations or deletions [6]. However, the exact functionality of PHF6 in T-ALL remains largely unclear. Nevertheless, recent studies in mice support a role of PHF6 in the regulation of leukemia stem cell activity [7, 8]. Interestingly, PHF6 has also been detected as a tumor promoting factor in B-ALL [9,10,11], suggesting a high degree of context specificity regarding the role of PHF6 in leukemia biology.

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Fig. 1: Phenotypic and molecular analysis of TLX1-driven zebrafish T-ALL.
Fig. 2: Comparative of gene expression analysis the phf6/hTLX1, hulk, hMYC, otg, and shrek T-ALL models.

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Acknowledgements

We would like to thank our zebrafish caretaker Karen Vermeulen for all her nurturing work. In addition, we would like to thank following agencies for funding reagents, zebrafish facility costs, and personnel expenses: FWO Vlaanderen (Fund for scientific research Flanders) (post)doctoral grants for SL, SV, and KD, FWO research project GO37918N; GOA: BOF16/GOA/023; BOF: 01J15119; Villa Joep; Kinderkankerfonds; Kom op tegen kanker: Emmanuel van der Schueren grant for LD and SL; Stichting tegen kanker project number: F/2014/373; the computational resources (Stevin Supercomputer Infrastructure) and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by Ghent University, FWO and the Flemish Government—department EWI. DML is funded by NIH (R01CA211734) and the MGH Research Scholars Program. JKF and his laboratory were supported by the OUHSC Jimmy Everest Section of Pediatric Hematology-Oncology and grants from Hyundai Hope On Wheels, the Oklahoma Center for the Advancement of Science and Technology (HRP-067), and an INBRE pilot project award from the National Institute of General Medical Sciences (P20 GM103447). JKF holds the Children’s Hospital Foundation E.L. and Thelma Gaylord Endowed Chair in Pediatric Hematology-Oncology. Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and used the Molecular Biology Shared Resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. These authors contributed equally: Kaat Durinck, Frank Speleman

Authors and Affiliations

  1. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

    Siebe Loontiens, Suzanne Vanhauwaert, Lisa Depestel, Givani Dewyn, Wouter Van Loocke, Pieter-Jan Volders, Volodimir Olexiouk, Pieter Van Vlierberghe, Kaat Durinck & Frank Speleman

  2. Cancer Research Institute Ghent (CRIG), Ghent, Belgium

    Siebe Loontiens, Suzanne Vanhauwaert, Lisa Depestel, Givani Dewyn, Wouter Van Loocke, Pieter-Jan Volders, Volodimir Olexiouk, Pieter Van Vlierberghe, Kaat Durinck & Frank Speleman

  3. Department of Pathology, Massachusetts General Hospital Research Institute, Boston, MA, 02114, USA

    Finola E. Moore, Elaine G. Garcia & David M. Langenau

  4. Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Finola E. Moore, Elaine G. Garcia & David M. Langenau

  5. Harvard Stem Cell Institute, Boston, MA, 02114, USA

    Finola E. Moore, Elaine G. Garcia & David M. Langenau

  6. Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA

    Finola E. Moore, Elaine G. Garcia & David M. Langenau

  7. Section of Pediatric Hematology-Oncology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Lance Batchelor, Chiara Borga, Barbara Squiban, Megan Malone-Perez & J. Kimble Frazer

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  1. Siebe Loontiens
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Correspondence to Kaat Durinck.

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Loontiens, S., Vanhauwaert, S., Depestel, L. et al. A novel TLX1-driven T-ALL zebrafish model: comparative genomic analysis with other leukemia models. Leukemia 34, 3398–3403 (2020). https://doi.org/10.1038/s41375-020-0938-2

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