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Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions

Oncogene volume 26, pages 2574–2584 (2007)Cite this article

Abstract

Acute myeloid leukemia (AML) 1 is often disrupted by chromosomal translocations generating oncogenic fusions in human leukemias. However, its role in epithelial cancers has not been extensively investigated. Herein, we show a marked accumulation of AML1 transcripts including a high frequency of a novel alternatively spliced AML1b transcript lacking exon 6 (AML1bDel179−242) in ovarian cancer patients. The increases in RNA transcripts for total wild-type AML1 and AML1bDel179−242 are associated with poor patient outcomes. We have shown that although both wild-type AML1b and AML1bDel179−242 are localized to nuclear speckles, AML1bDel179−242 was observed to have dramatically reduced transactivation potential with the plasminogen activator inhibitor-1 promoters and behaved as a weak dominant negative of wild-type AML1b. Wild-type AML1b was found to inhibit the growth of immortalized ovarian epithelial cells (T29) decreasing colony-forming ability. Moreover, we have identified a novel function of AML1b where it inhibits ovarian cell migration. In contrast, AML1bDel179−242 has lost the ability to inhibit both ovarian cell proliferation and migration indicating that the functional effects observed with wild-type AML1b are dependent on amino acids 179–242. Collectively, these studies suggest that deregulated alternative splicing of AML1b transcripts may potentially contribute to the pathophysiology of ovarian cancers.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

AML:

acute myeloid leukemia

RHD:

runt homology domain

TGFβ:

transforming growth factor β

OSE:

ovarian epithelial cells

PAI-1:

plasminogen activator inhibitor-1

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Acknowledgements

This work was supported by the NCI P50 CA083639, P30 CA16672 and P01 CA64602 to GBM.

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Authors and Affiliations

  1. Department of Molecular Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    M Nanjundan, F Zhang & G B Mills

  2. Department of Gynecologic Oncology, MD Anderson Cancer Center, TX, USA

    R Schmandt

  3. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA

    K Smith-McCune

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  1. M Nanjundan
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  2. F Zhang
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  4. K Smith-McCune
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Correspondence to M Nanjundan.

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Nanjundan, M., Zhang, F., Schmandt, R. et al. Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions. Oncogene 26, 2574–2584 (2007). https://doi.org/10.1038/sj.onc.1210067

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