1. ¹Department of Molecular Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
2. ²Department of Gynecologic Oncology, MD Anderson Cancer Center, TX, USA
3. ³Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA

Correspondence: Dr M Nanjundan, Department of Molecular Therapeutics, MD Anderson Cancer Center, University of Texas, 7435 Fannin Street, Houston, TX 77054, USA. E-mail: mnanjund@mdanderson.org

Received 27 June 2006; Revised 28 August 2006; Accepted 1 September 2006; Published online 30 October 2006.

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 AML1b^Del179-242 are associated with poor patient outcomes. We have shown that although both wild-type AML1b and AML1b^Del179-242 are localized to nuclear speckles, AML1b^Del179-242 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.