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 language | English (US) |
---|---|
Pages (from-to) | 2574-2584 |
Number of pages | 11 |
Journal | Oncogene |
Volume | 26 |
Issue number | 18 |
DOIs | |
State | Published - Apr 19 2007 |
Externally published | Yes |
Keywords
- AML1
- Ovarian cancers
- Splicing
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research