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Acute Leukemias

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

Leukemia volume 28, pages 1259–1270 (2014)Cite this article

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Abstract

Transient leukemia (TL) is evident in 5–10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. Although GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1Δe2 knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.

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Acknowledgements

The authors thank J Strouboulis and E Karkoulia for providing BioGata1/Gata1s ESCs. J Schoening for general lab support; Drs K Weber and B Fehse for providing plasmids; Dr A Mirenska for chip cytometry data analysis; Dr R Geffers for microarray analysis. AM, LS, SE and TD were supported by the Hannover Biomedical Research School. JHK is a fellow of the Emmy Noether-Programme from the German Research Foundation (KL-2374/2-1). This work was supported by a grant to JHK from the German Research Foundation (KL-2374/1-1).

Author contributions

AM, KR and TD performed experiments; LS, SE, JX, ZS and GJ performed experiments and analyzed results. AM and JHK analyzed and interpreted results, prepared the figures and wrote the manuscript; JHK designed the research. DR and JH provided patient material and revised the manuscript. IR, CH, KR, PV, ZL and SO analyzed and interpreted results and revised the manuscript. GH provided access and support to laboratory equipment and revised the manuscript.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    A Maroz, L Stachorski, S Emmrich, K Reinhardt, S Käbler, T Dertmann, D Reinhardt & J-H Klusmann

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

    J Xu, Z Shao & S Orkin

  3. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    J Xu, Z Shao & S Orkin

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

    J Xu, Z Shao & S Orkin

  5. Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

    J Hitzler

  6. Oxford University Department of Paediatrics, Childrens Hospital and Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, UK

    I Roberts

  7. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    P Vyas & G Juban

  8. Department of Haematology, Oxford University Hospital, NHS Trust, Oxford, UK

    P Vyas & G Juban

  9. Department of Pediatric Pneumology, Hannover Medical School, Hannover, Germany

    C Hennig & G Hansen

  10. Division of Genetics, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Z Li

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CH has filed patents regarding chip cytometry. The other authors declare no competing financial interests.

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Maroz, A., Stachorski, L., Emmrich, S. et al. GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia. Leukemia 28, 1259–1270 (2014). https://doi.org/10.1038/leu.2013.373

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