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Acute Leukemias

Epigenetic regulation of GATA2 and its impact on normal karyotype acute myeloid leukemia

Leukemia volume 28, pages 1617–1626 (2014)Cite this article

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Abstract

The GATA2 gene encodes a zinc-finger transcription factor that acts as a master regulator of normal hematopoiesis. Mutations in GATA2 have been implicated in the development of myelodysplastic syndrome and acute myeloid leukemia (AML). Using RNA sequencing we now report that GATA2 is either mutated with a functional consequence, or expressed at low levels in the majority of normal karyotype AML (NK-AML). We also show that low-GATA2-expressing specimens (GATA2low) exhibit allele-specific expression (ASE) (skewing) in more than half of AML patients examined. We demonstrate that the hypermethylation of the silenced allele can be reversed by exposure to demethylating agents, which also restores biallelic expression of GATA2. We show that GATA2low AML lack the prototypical R882 mutation in DNMT3A frequently observed in NK-AML patients and that The Cancer Genome Atlas AML specimens with DNMT3A R882 mutations are characterized by CpG hypomethylation of GATA2. Finally, we validate that several known missense single-nucleotide polymorphisms in GATA2 are actually loss-of-function variants, which, when combined with ASE, represent the equivalent of homozygous GATA2 mutations. From a broader perspective, this work suggests for the first time that determinants of ASE likely have a key role in human leukemia.

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Acknowledgements

We would like to thank Jana Krosl and Josette-Renée Landry for helpful discussions and comments on the manuscript and Manish Goel, Patrick Gendron, Pierre Chagnon, Marianne Arteau and Raphaëlle Lambert for excellent technical assistance. We also wish to thank Dr Hamish Scott and the Louisiana State University Health Sciences Center at Shreveport for the generous donation of reagents and we acknowledge the TCGA for making data from their project publicly available. This research was supported by funding from the Cole Foundation and FRSQ (BTW and MC), NSERC (BTW) and Genome Quebec (BTW, SL, JH and GS). Support from the BCLQ is also gratefully acknowledged and we also wish to acknowledge the contribution of all of the courageous patients who provided samples used in this study. Correspondence and requests for materials should be addressed to BTW (brian.wilhelm@umontreal.ca).

Author contributions

BTW designed and supervised the experimental work with help from MC while MC and AF performed the experimental work presented; GG, MC and BTW analyzed the data with help from SL; MC and GG drafted the paper with revisions by BTW, GS, JH and SL.

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Authors and Affiliations

  1. Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada

    M Celton, A Forest, G Gosse, S Lemieux, J Hebert, G Sauvageau & B T Wilhelm

  2. Laboratory for high-throughput genomics, Montreal, Québec, Canada

    M Celton, A Forest, G Gosse & B T Wilhelm

  3. INRA, UMR1083, Sciences Pour l'Oenologie, Montpellier, France

    M Celton

  4. Laboratory for Functional and Structural Bioinformatics, Montreal, Québec, Canada

    S Lemieux

  5. Leukemia Cell Bank of Quebec and Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Québec, Canada

    J Hebert & G Sauvageau

  6. Laboratory for Molecular Genetics of Stem Cells, Montreal, Québec, Canada

    G Sauvageau

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  1. M Celton
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  2. A Forest
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Correspondence to B T Wilhelm.

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Celton, M., Forest, A., Gosse, G. et al. Epigenetic regulation of GATA2 and its impact on normal karyotype acute myeloid leukemia. Leukemia 28, 1617–1626 (2014). https://doi.org/10.1038/leu.2014.67

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