Investigating the roles of splicing factor mutations in lung adenocarcinomas and myeloid neoplasms

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NCI	DIR-12

* FARE Award Winner

Authors

• D Liang Fei
• S Prasad
• J Yu
• H Motowski
• H Varmus

Abstract

Putative "driver" mutations in genes encoding splicing factors---including recurrent mutations in U2AF1, which encodes a component of the U2 auxiliary factor to regulate pre-mRNA splicing---have been identified in myeloid dysplasias (MDS), related neoplasms, and lung adenocarcinomas. To study the functional impact of U2AF1 mutations, we have created transgenic mice carrying conditional mutant alleles at the endogenous U2AF1 locus, and isogenic human bronchial epithelial cells (HBECs) encoding the mutant splicing factor at the endogenous locus. In U2AF1-mutant HBECs, we have observed changes in pre-mRNA splicing of RNA from many genes. Using the mouse model we created, we found that bone marrow cells expressing the U2AF1 mutation had a modest but statistically significant reduction in their ability to form monocyte and granulocyte colonies in culture. We also observed a low ratio of mutant to wild-type U2AF1 RNA in blood cells, implying that expression of U2AF1-S34F affects normal hematopoiesis or survival of blood cells in mice - a phenomenon that may be related to the role of mutant U2AF1 in myeloid dysplasias. We are continuing to characterize these cell lines and mice, molecularly and phenotypically, in hopes of understanding the oncogenic role of the U2AF1 mutation in the pathogenesis of cancer.

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