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Decreased intranuclear mobility of acute myeloid leukemia 1-containing fusion proteins is accompanied by reduced mobility and compartmentalization of core binding factor β

Oncogene volume 25, pages 3982–3993 (2006)Cite this article

Abstract

Acute myeloid leukemia 1 (AML1) gene on chromosome 21 is involved in several chromosomal translocations, including t(8;21) and t(16;21), that produce chimeric fusion proteins AML1–eight twenty-one (ETO) and AML–myeloid transforming gene chromosome 16 (MTG16), which contribute to leukemogenesis. The molecular basis for the leukemogenic effects of these fusion proteins is incompletely understood. Using gel-shift assay, we showed that AML1–ETO and AML1–MTG16 bound to a series of AML1 consensus DNA-binding sites with different affinities. Using fluorescence recovery after photobleaching (FRAP), we demonstrated that a fusion of AML1 with ETO or MTG16 exhibits reduced intranuclear mobility compared with wild-type AML1 or either fusion partner. The dimerization domain (nervy homology region 2) of ETO is responsible for the reduced mobility of AML1–ETO. Dual FRAP studies revealed that CBFβ colocalized with AML1–ETO within the nucleus, resulting in reduced mobility of CBFβ. Therefore, AML1 fusion proteins may interfere with normal AML1 function due to aberrant nuclear dynamics, which leads to spatial and temporal sequestration of CBFβ and perhaps other coregulators critical for myeloid differentiation.

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Acknowledgements

We thank Dr Hisamaru Hirai (University of Tokyo, Tokyo, Japan) for AML1A, AML1-EVI1 and EVI1 vectors; Dr Scott W Hiebert (Vanderbilt University School of Medicine, Nashville, TN, USA) for AML1B and ETO vectors; Dr Pu P Liu (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA) for CBFβ and CBFβ-MYH11 vectors; Dr Fumiko Morohoshi (National Cancer Center Research Institute, Tokyo, Japan) for MTG16a and MTGR1 vectors and Dr Robynn V Schillace (Oregon Health and Sciences University, Portland, OR) for MTG16b vector. We greatly appreciate the helpful discussions of Dr Michael Mancini and the technical assistance of Dr David Stewart from the Department of Molecular and Cellular Biology of Baylor College of Medicine. This work was supported in part by grant #IRG 93-034-06 (to SD) from the American Cancer Society (ACS), Chao Award (to SD) from the Department of Medicine of Baylor College of Medicine and R21 grant CA119080 (to SD) from the National Cancer Institute (NCI).

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  1. Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA

    J Qiu, D J Tweardy & S Dong

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    J Wong

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  1. J Qiu
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Correspondence to S Dong.

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Qiu, J., Wong, J., Tweardy, D. et al. Decreased intranuclear mobility of acute myeloid leukemia 1-containing fusion proteins is accompanied by reduced mobility and compartmentalization of core binding factor β. Oncogene 25, 3982–3993 (2006). https://doi.org/10.1038/sj.onc.1209431

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