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

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 Del179À242 ) in ovarian cancer patients. The increases in RNA transcripts for total wild-type AML1 and AML1b Del179À242 are associated with poor patient outcomes. We have shown that although both wild-type AML1b and AML1b Del179À242 are localized to nuclear speckles, AML1b Del179À242 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 Del179À242 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.

Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice

“…18,[27][28][29][30] Although no RUNX1a ortholog was found in mice, a truncated isoform Runx1bEx6e was identified in a mouse embryonic cDNA library. 39 It was a transcript from P2, and had an extended exon 6 with an additional 63 amino acids in the C terminus.…”

“…However, human RUNX1b without exon 6 showed a dominant-negative effect over full-length RUNX1b in a luciferase assay using the plasminogen activator inhibitor-1 promoter as a reporter and the immortalized ovarian surface epithelial cell T29 line. 27 The difference may be due to the presence of different cooperating factors in different cell lineages and different cis-acting elements adjacent to the Runx1 binding sites in promoters.…”

“…18,[27][28][29][30] Changes of RUNX1 isoform ratios or novel isoforms are also found in various malignancies. 24,27,29,48 In acute myeloid leukemia, t(8;21) is a common form of chromosome translocation. It generates fusion transcripts between exon 5 of human RUNX1 and exon 2 of RUNX1T1.…”

“…27,32 However, the RUNX1 isoforms generated by alternative splicing of exon 6 have not been thoroughly described and characterized.…”

New Strategies in Non–Small Cell Lung Cancer: Improving Outcomes in Chemoradiotherapy for Locally Advanced Disease

“…The hemodynamic characteristics of tumor microvasculature can be noninvasively assessed by dynamic contrastenhanced CT (DCE-CT). DCE-CT has been shown to be a useful method for monitoring lung tumor vascularity (49)(50)(51)(52), confirming the general value of tumor vascular assessment in this population.…”