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Transcriptional control and signal transduction, cell cycle

AMKL chimeric transcription factors are potent inducers of leukemia

Leukemia volume 31, pages 2228–2234 (2017)Cite this article

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Abstract

Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathological including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2, which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain-of-function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathological drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies.

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Acknowledgements

We would like to thank the staff of Flow Cytometry Core, Veterinary Pathology, as well as the Hartwell Center for Biotechnology and Bioinformatics of St Jude Children’s Research Hospital. Jinghui Zhang and the department of computational biology graciously provided previously established bioinformatic pipelines and support. We thank Charles J Sherr, Thomas A Look and Jeffery M Klco for their comments on the manuscript. This work was supported by grants from the Eric Trump Foundation, Gabrielle Angel Foundation and the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital.

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Authors and Affiliations

  1. Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA

    J Dang, S Nance, C Koss & T A Gruber

  2. Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA

    J Ma, J Cheng, M P Walsh, G Song, A L Gedman, J R Downing & T A Gruber

  3. Department of Veterinary Pathology Core, St Jude Children’s Research Hospital, Memphis, TN, USA

    P Vogel

  4. Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, TN, USA

    J Easton & M Rusch

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Correspondence to T A Gruber.

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Dang, J., Nance, S., Ma, J. et al. AMKL chimeric transcription factors are potent inducers of leukemia. Leukemia 31, 2228–2234 (2017). https://doi.org/10.1038/leu.2017.51

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