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Acute Leukemias

GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia

Leukemia volume 27, pages 578–585 (2013)Cite this article

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Abstract

The t(1;19) translocation in pediatric pre-B-cell acute lymphoblastic leukemia (ALL) fuses the genes, which encode the transcriptional activator E2A and homeobox pre-B-cell leukemia transcription factor 1 (PBX1), resulting in expression of the chimeric transcription factor E2A-PBX1. E2A-PBX1 can promote cell transformation both in vitro and in vivo; however, the mechanisms by which E2A-PBX1 contributes to malignancy merit further investigation. In the current work we report, for the first time, a physical and functional interaction between the SPT3-TAFII31-GCN5L acetylase (STAGA) complex and E2A-PBX1. STAGA, and its acetyltransferase subunit GCN5, directly interacted with the E2A portion of E2A-PBX1. GCN5 acetylated E2A-PBX1 and increased the stability of E2A-PBX1 protein in cells. Moreover, the GCN5 inhibitor α-methylene-γ-butyrolactone 3 (MB-3) decreased E2A-PBX1 acetylation and E2A-PBX1 protein levels in leukemic cells, indicating that GCN5 inhibitors have potential value as therapeutic agents for ALL. In addition, we show that the E3 ubiquitin ligase HDM2 potentiates the degradation of E2A-PBX1. We suggest that dynamic regulation of E2A-PBX1 protein levels in vivo has a fundamental role in ALL.

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Acknowledgements

The authors thank Dr DP LeBrun, Dr FB Hillgarter, Dr P Puigserver, Dr PA Cole and Dr D Bohmann for generously providing expression plasmids described in Materials and methods. Dr RG Roeder is acknowledged for the kind gifts of antibodies and the fh:SPT3 stable cell line. Dr K Pokrovskaja and A-C Bjorklund are gratefully acknowledged for technical assistance with primary ALL cell culture. This work was supported by grants from the Swedish Research Council, Swedish Cancer Society, the Swedish Children’s Cancer Foundation and Radiumhemmets forskningsfonder. MJL was supported by a fellowship from the Swedish Children’s Cancer Foundation.

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Authors and Affiliations

  1. Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    T Holmlund, M J Lindberg & A E Wallberg

  2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    D Grander

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  1. T Holmlund
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Correspondence to A E Wallberg.

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Holmlund, T., Lindberg, M., Grander, D. et al. GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia. Leukemia 27, 578–585 (2013). https://doi.org/10.1038/leu.2012.265

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