Antisense (AS) oligodeoxynucleotides (ODN) have been widely employed to perturb gene expression, and elucidate gene function in a laboratory setting. More recently my group, and others, have reported in vitro and in vovo models which demonstrate the potential therapeutic utility of AS ODN. Based on this body of work, we have instituted Phase I trials of AS ODN for the treatment of human leukemias at the Hospital of the University of Pennsylvania. While the results of these initial clinical trials may be viewed as encouraging, we appreciate that this approach to anti-cancer therapeutics can only be made practical if a more basic understanding of the """"""""antisense mechanism"""""""" is developed. The long term goals of this project are to enrich our understanding of how AS ODN impair mRNA utilization in living cells, and to then use this knowledge in the development of ODN therapies for human leukemias. To study the mechanisms of ODN pertubation of gene function we will employ normal and neoplastic human hematopoietic cells as a model system. Specifically, we will examine how AS molecules impair the utilization of Vav mRNA in cells of this type. Vav protein is the product of a protooncogene which functions as an important signalling protein in hematopoietic cells. Our preliminary data, discussed below, suggests that Vav mRNA represents a rational therapeutic target in certain human leukemias. Accordingly, these studies will have both basic and translational relevance and will hopefully culminate in the institution of a Phase I clinical protocol for the treatment of human leukemia.
Three specific aims have been developed to help us achieve this project's long term goals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA072765-05S1
Application #
6491048
Study Section
Project Start
2001-07-16
Project End
2003-06-30
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kini, Hemant K; Kong, Jian; Liebhaber, Stephen A (2014) Cytoplasmic poly(A) binding protein C4 serves a critical role in erythroid differentiation. Mol Cell Biol 34:1300-9
Ji, Xinjun; Wan, Ji; Vishnu, Melanie et al. (2013) ?CP Poly(C) binding proteins act as global regulators of alternative polyadenylation. Mol Cell Biol 33:2560-73
Ji, Xinjun; Kong, Jian; Liebhaber, Stephen A (2011) An RNA-protein complex links enhanced nuclear 3' processing with cytoplasmic mRNA stabilization. EMBO J 30:2622-33
Jin, Shenghao; Zhao, Huiwu; Yi, Yan et al. (2010) c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis. J Clin Invest 120:593-606
Deleavey, Glen F; Watts, Jonathan K; Alain, Tommy et al. (2010) Synergistic effects between analogs of DNA and RNA improve the potency of siRNA-mediated gene silencing. Nucleic Acids Res 38:4547-57
Waggoner, Shelly A; Johannes, Gregg J; Liebhaber, Stephen A (2009) Depletion of the poly(C)-binding proteins alphaCP1 and alphaCP2 from K562 cells leads to p53-independent induction of cyclin-dependent kinase inhibitor (CDKN1A) and G1 arrest. J Biol Chem 284:9039-49
Rudnick, Stephen I; Swaminathan, Jyothishmathi; Sumaroka, Marina et al. (2008) Effects of local mRNA structure on posttranscriptional gene silencing. Proc Natl Acad Sci U S A 105:13787-92
Flagler, K; Alexeev, V; Pierce, E A et al. (2008) Site-specific gene modification by oligodeoxynucleotides in mouse bone marrow-derived mesenchymal stem cells. Gene Ther 15:1035-48
Pattanayak, Vikram; Gifford, Lida K; Lu, Ponzy et al. (2008) Observed versus predicted structure of fluorescent self-quenching reporter molecules (SQRM): caveats with respect to the use of ""stem-loop"" oligonucleotides as probes for mRNA folding. RNA 14:657-65
Tang, XinJing; Swaminathan, Jyothishmathi; Gewirtz, Alan M et al. (2008) Regulating gene expression in human leukemia cells using light-activated oligodeoxynucleotides. Nucleic Acids Res 36:559-69

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