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, Gordon Mills

Research output: Contribution to journalArticle

9 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Ovarian Neoplasms
Cell Movement
Genetic Translocation
Plasminogen Activator Inhibitor 1
Alternative Splicing
Acute Myeloid Leukemia
Transcriptional Activation
Exons
Neoplasms
Leukemia
Epithelial Cells
Cell Proliferation
RNA
Amino Acids
Growth

Keywords

  • AML1
  • Ovarian cancers
  • Splicing

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions. / Nanjundan, M.; Zhang, F.; Schmandt, R.; Smith-Mccune, K.; Mills, Gordon.

In: Oncogene, Vol. 26, No. 18, 19.04.2007, p. 2574-2584.

Research output: Contribution to journalArticle

Nanjundan, M. ; Zhang, F. ; Schmandt, R. ; Smith-Mccune, K. ; Mills, Gordon. / Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions. In: Oncogene. 2007 ; Vol. 26, No. 18. pp. 2574-2584.
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