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Transcriptional Control and Deregulation

Discovery of epigenetically silenced genes in acute myeloid leukemias

Abstract

The demethylating 5-aza-2′deoxycytidine (DAC) and the histone deacetylase inhibitor (HDACi) suberoyl anilide bishydroxamide (SAHA) possess potent antitumorigenic properties in myeloid disorders. However, the transcriptome alterations mediated by these drugs are poorly understood. We analyzed the transcriptional effects of DAC and SAHA in the AML cell line KG-1. Microarray analyses revealed 76 genes expressed in normal CD34+ cells, absent in KG-1 cells but whose expression was induced after drug treatment. A total of 39 of these genes harbored CpG islands in their promoters. We examined the expression level of these genes in 120 AML patient samples representing diverse karyotpyes. Gas2l1, tfIIs, ehd3, enolase 2, mx1, dral, astml and pxdn were diminished across all AML karyotypes examined. Ehd3 was methylated in 63% of AML patients examined. This methylation was lost upon complete remission, and not observed in normal CD34+ cells. CD34+ cells expressed ehd3 at approximately 10-fold higher levels than AML samples. Another highlighted gene, α-catenin, is located at q31 of chromosome 5. Analyses of 29 5q- AML/myelodysplastic syndrome (MDS) samples revealed marked decreases in expression of α-catenin, compared to non-5q- MDS samples (6.6±9-fold). However, no methylation was detected, suggesting indirect effects of these drugs on the expression of α-catenin.

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Acknowledgements

This work was supported in part by NIH grants, Inger Fund, Parker Hughes Trust and C&H Koeffler Foundation. Dedicated to the memory of David Golde, a friend and mentor. HPK holds the Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center and is a member of the Jonsson Comprehensive Cancer Center and the Molecular Biology Institute, UCLA.

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Correspondence to H P Koeffler.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Desmond, J., Raynaud, S., Tung, E. et al. Discovery of epigenetically silenced genes in acute myeloid leukemias. Leukemia 21, 1026–1034 (2007). https://doi.org/10.1038/sj.leu.2404611

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