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Myelodysplasias

Genome-wide profiling reveals epigenetic inactivation of the PU.1 pathway by histone H3 lysine 27 trimethylation in cytogenetically normal myelodysplastic syndrome

Leukemia volume 27, pages 1291–1300 (2013)Cite this article

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Abstract

Cytogenetically normal myelodysplastic syndrome (CN-MDS) can pose diagnostic challenges and its pathogenetic mechanism remains elusive. By focusing on cytogenetically normal refractory cytopenia with multilineage dysplasia (CN-RCMD), a subtype of MDS, our genome-wide profiling showed ∼4600 annotated gene promoters with increased Histone H3 lysine 27 trimethylation (H3K27me3) in CN-RCMD, when compared with normal controls. Computational analysis revealed a statistically significant enrichment of the PU.1-binding DNA motif (PU-box) in the regions with increased H3K27me3. An inverse relationship between the levels of H3K27me3 and the levels of PU.1 binding and its downstream myeloid gene expressions was observed. Whole-exome sequencing analysis and Sanger sequencing analysis revealed some recurrent mutations, but no mutations in the PU.1 regulatory regions or in the EZH1/2, H3K27 methytransferase encoding genes. Using an MDS-derived erythroid/myeloid line and primary MDS bone marrow cells, we demonstrated that H3K27me3 inhibitors can increase the expression of PU.1 and its downstream genes and also promote cell differentiation via reducing H3K27me3 at the PU.1 gene locus. Finally, ectopic expression of PU.1 significantly inhibited proliferation of the MDS-derived cell line. Based on these data, we propose a hypothetical model of epigenetic inactivation of the PU.1 pathway due to increased H3K27me3 in some cases of CN-RCMD.

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Acknowledgements

We wish to thank Ms Ana Rodrigues in Bioinformatics for helping with computational analyses, and Ms Mandy Roteman, Ms Kelly Doston and Ms Christine A Feak for their assistance.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    J X Cheng, E L Kleinbrink, E Grimley & R Knibbs

  2. Department of Pathology, University of Chicago, Chicago, IL, USA

    J Anastasi & J W Vardiman

  3. School of Life Sciences, University of Nevada, Las Vegas, NV, USA

    K Watanabe & Q J Shen

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  1. J X Cheng
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Correspondence to J X Cheng.

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Cheng, J., Anastasi, J., Watanabe, K. et al. Genome-wide profiling reveals epigenetic inactivation of the PU.1 pathway by histone H3 lysine 27 trimethylation in cytogenetically normal myelodysplastic syndrome. Leukemia 27, 1291–1300 (2013). https://doi.org/10.1038/leu.2013.45

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