University of South Florida

Cancer Biology Ph.D. Program at the

Meera Nanjundan , Ph.D. Assistant Professor Division of Cell, Microbiology and Molecular Biology USF Department of Biology E-mail: mnanjund@cas.usf.edu Phone: 813-974-8133

Training
Ph.D.: University of Western Ontario, London, Ontario, CANADA (2001)
Postdoctoral Fellow: The Scripps Research Institute, La Jolla, California (2001-03)
Postdoctoral Fellow: M.D. Anderson Cancer Center (2003-07)
Research Assistant Professor: M.D. Anderson Cancer Center (2007)

Research Interests

Role of Aberrant Splicing in Lung and other Cancers

We have identified a number of genes within regions of genomic aberration in ovarian cancer as well as lung cancer that are aberrantly spliced as defined by the presence of frequent splice variants using cryptic splice sites rarely if ever used in normal cells. Alternative splicing of mRNA transcripts generates additional genomic complexity from the low number of genes present in the human genome. Specific alterations in splicing patterns in cancer may alter specific events during initiation and progression. Within the 3q26.2 genomically amplified region, EVI1 is highly and selectively amplified at the DNA, RNA, and protein level. Strikingly, EVI1 is aberrantly spliced resulting in production of MDS1/EVI1 (a readthrough encompassing EVI1 and the nearby MDS1 gene) and Del190-515 splice forms to a high frequency in >90% of advanced stage serous epithelial ovarian cancers as well as lung cancers. EVI1 and its splice variants play distinct roles during tumor initiation and progression depending on the cellular context based on altered signaling and functional outcomes. The effect of EVI1 is similar to the well-established dual effect of TGFb (inhibits growth inhibitor at early stages and promotes metastasis at late stages). Differential effects of the most highly expressed EVI1 splice variants on cellular function during tumor initiation and progression likely contribute to patient outcome. Thus, in addition to copy number aberrations, deregulated mRNA splicing leads to changes in protein function, likely altering prognosis and potentially response to chemotherapeutic agents. We propose that a detailed understanding of the regulatory mechanisms underlying aberrant splicing of EVI1 and other genes will lead to the development of molecular markers that will improve methods for early cancer detection, determining prognosis, and identifying novel targets. mRNA splicing is a critical step in post-transcriptional modification of RNA. Since aberrant splicing is not limited to EVI1 at 3q26.2 but to additional amplified genes in ovarian and lung cancer, this appears to be a global phenomenon. The mechanisms responsible for these tumor-specific changes currently remain undefined and thus, the proposed studies are likely to provide a mechanistic basis for the investigation of genomically amplified genes associated with aberrant splicing. The cancer genome atlas project which will perform whole genome Exon array analysis in multiple cancers including lung will likely identify differential splicing patterns, establish genes participating in various steps of lung cancer development, and reveal the consequences of their dysregulated splicing.

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This search will be conducted at the US National Library of Medicine (NLM) and PubMed.

Selected Publications
1. Nanjundan M, Cheng KW, Zhang F, Lahad J, Kuo WL, Schmandt R, Smith-McCune K, Fishman D, Gray JW, Mills GB. Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis Mol. Oncology, 2008: Vol 2: 164-181

2. Hennessy BT, Murph M, Nanjundan M, Carey M, Auersperg N, Almeida J, Coombes KR, Liu J, Lu Y, Gray JW, Mills GB. Ovarian cancer: linking genomics to new target discovery and molecular markers--the way ahead. Adv Exp Med Biol. 2008;617:23-40.

3. Nanjundan M, Nakayama Y, Cheng KW, Lahad J, Liu J, Lu K, Kuo WL, Smith-McCune K, Fishman D, Gray JW, Mills GB. Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer. Cancer Res. 2007 Apr 1;67(7):3074-84.

4. Nanjundan M, Zhang F, Schmandt R, Smith-McCune K, Mills GB. Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions. Oncogene. 2007 Apr 19;26(18):2574-84. Epub 2006 Oct 30.

5. Hennessy BT, Nanjundan M, Cheng KW, Nolden L, Mills GB. Identification of remodeling and spacing factor 1 (rsf-1, HBXAP) at chromosome 11q13 as a putative oncogene in ovarian cancer. Eur J Hum Genet. 2006 Apr;14(4):381-3.