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Shared acquired genomic changes in zebrafish and human T-ALL

Oncogene volume 30, pages 4289–4296 (2011)Cite this article

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging clinical entity with high rates of induction failure and relapse. To discover the genetic changes occurring in T-ALL, and those contributing to relapse, we studied zebrafish (Danio rerio) T-ALL samples using array comparative genomic hybridization (aCGH). We performed aCGH on 17 T-ALLs from four zebrafish T-ALL models, and evaluated similarities between fish and humans by comparing all D. rerio genes with copy number aberrations (CNAs) with a cohort of 75 published human T-ALLs analyzed by aCGH. Within all D. rerio CNAs, we identified 893 genes with human homologues and found significant overlap (67%) with the human CNA dataset. In addition, when we restricted our analysis to primary T-ALLs (14 zebrafish and 61 human samples), 10 genes were recurrently altered in >3 zebrafish cancers and ⩾4 human cases, suggesting a conserved role for these loci in T-ALL transformation across species. We also conducted iterative allo-transplantation with three zebrafish malignancies. This technique selects for aggressive disease, resulting in shorter survival times in successive transplant rounds and modeling refractory and relapsed human T-ALL. Fifty-five percent of original CNAs were preserved after serial transplantation, demonstrating clonality between each primary and passaged leukemia. Cancers acquired an average of 34 new CNAs during passaging. Genes in these loci may underlie the enhanced malignant behavior of these neoplasias. We also compared genes from CNAs of passaged zebrafish malignancies with aCGH results from 50 human T-ALL patients who failed induction, relapsed or would eventually relapse. Again, many genes (88/164) were shared by both datasets. Further, nine recurrently altered genes in passaged D. rerio T-ALL were also found in multiple human T-ALL cases. These results suggest that zebrafish and human T-ALLs are similar at the genomic level, and are governed by factors that have persisted throughout evolution.

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Acknowledgements

We thank Brett Milash for bioinformatics analyses, Ken Boucher for statistical expertise, and Bradley Demarest for assistance with figure preparation. NST was supported by NIAID award R21-AI079784 and the Huntsman Cancer Foundation. JKF was supported by Eunice Kennedy Shriver NICHD award K08-HD053350, the CHRC at the University of Utah, and the PCMC Foundation. Huntsman Cancer Institute core facilities supported by NCI P30-CA042014 also contributed to this work.

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Author notes

  1. N S Trede and J K Frazer: These authors share senior authorship of this work.

Authors and Affiliations

  1. Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA

    L A Rudner, D F Bradley, A C H Smith, J D Schiffman, N S Trede & J K Frazer

  2. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA

    K H Brown, K P Dobrinski & C Lee

  3. University of Texas at Brownsville, Brownsville, TX, USA

    M I Garcia

  4. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    J M Downie, N D Meeker, J D Schiffman, N S Trede & J K Frazer

  5. Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA, USA

    A T Look & A Gutierrez

  6. St Jude Children's Research Hospital, Memphis, TN, USA

    J R Downing & C G Mullighan

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  1. L A Rudner
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  2. K H Brown
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Correspondence to J K Frazer.

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Rudner, L., Brown, K., Dobrinski, K. et al. Shared acquired genomic changes in zebrafish and human T-ALL. Oncogene 30, 4289–4296 (2011). https://doi.org/10.1038/onc.2011.138

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  • DOI: https://doi.org/10.1038/onc.2011.138

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