The inhibitor of apoptosis protein Survivin is overexpressed in most cancers and hematologic malignancies and is an indicator of aggressive disease and poor outcome. Survivin is widely expressed during development but not in most adult tissues, making it an attractive therapeutic target. We were the first to demonstrate that Survivin is expressed and growth factor regulated in normal hematopoietic stem cells (HSC). New evidence from several areas now supports a critical role in preservation of cell viability and maintenance of normal mitosis. This leads to 2 hypotheses. First, Survivin is a normal regulator of HSC and Survivin targeted therapies may have hematologic toxicities. We will modulate Survivin expression in adult mouse HSC using retroviruses and quantitate its effects on hematopoiesis by competitive repopulation following transplantation and its role as a potential oncogene. Second, Survivin is a critical and multifaceted mediator of the cell death versus cell division decisions in HSC and understanding Survivin pathways will identify new therapeutic targets. We will investigate signaling pathways that regulate Survivin production and the molecular/biochemical relationships between Survivin and the intracellular regulators of apoptosis and cell cycle, i.e., cyclins, cyclin dependent kinases (cdks), cdk inhibitors (CDKIs), and the p53 family of tumor suppressors. We will investigate these interactions in normal primary HSC, in novel hematopoietic and nonhematopoietic cell line models, in which Survivin expression/disruption can be transiently or conditionally modulated, and in mice, in which genes for cell cycle and apoptosis related proteins have been deleted. Understanding the hematologic consequence of normal and abnormal Survivin expression and defining the molecular mechanisms of act of Survivin in regulating cell survival, cell cycle progression, and cell division in normal HSC will provide important information on normal cell survival and cell cycle regulation critical to the design of safe and efficacious Survivin-based therapies that target cell cycle and apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079654-04
Application #
7261923
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$321,078
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Fukuda, S; Hoggatt, J; Singh, P et al. (2015) Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1. Leukemia 29:433-40
Singh, Pratibha; Hoggatt, Jonathan; Hu, Peirong et al. (2012) Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells. Blood 119:1671-82
Pelus, L M; Hoggatt, J; Singh, P (2011) Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery. Cell Prolif 44 Suppl 1:22-9
Srirangam, Anjaiah; Milani, Monica; Mitra, Ranjana et al. (2011) The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin. J Thorac Oncol 6:661-70
Hoggatt, J; Pelus, L M (2010) Eicosanoid regulation of hematopoiesis and hematopoietic stem and progenitor trafficking. Leukemia 24:1993-2002
Hoggatt, Jonathan; Singh, Pratibha; Sampath, Janardhan et al. (2009) Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 113:5444-55
Fukuda, Seiji; Singh, Pratibha; Moh, Akira et al. (2009) Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3. Blood 114:394-403
Guzman, Javier Rivera; Fukuda, Seiji; Pelus, Louis M (2009) Inhibition of caspase-3 by Survivin prevents Wee1 Kinase degradation and promotes cell survival by maintaining phosphorylation of p34Cdc2. Gene Ther Mol Biol 13B:264-273
Pelus, Louis M (2008) Peripheral blood stem cell mobilization: new regimens, new cells, where do we stand. Curr Opin Hematol 15:285-92
Wang, Zhanxiang; Pelus, Louis M (2008) Disruption of Survivin in K562 cells elevates telomerase activity and protects cells against apoptosis induced by the Bcr-abl kinase inhibitor STI571. Cancer Ther 6:603-610

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