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

M. Nanjundan, F. Zhang, R. Schmandt, K. Smith-Mccune, G. B. Mills

    Research output: Contribution to journalArticle

    9 Scopus citations

    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 (AML1b Del179-242) 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, AML1b Del179-242 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.

    Original languageEnglish (US)
    Pages (from-to)2574-2584
    Number of pages11
    JournalOncogene
    Volume26
    Issue number18
    DOIs
    StatePublished - Apr 19 2007

    Keywords

    • AML1
    • Ovarian cancers
    • Splicing

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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