The past several years have seen a tremendous expansion in the field of stem cell biology. Numerous advances have occurred in understanding the biological relevance of stem cells, as well as their specific molecular properties. An important part of this new era in stem cell science relates directly to hematologic malignancies. Recent studies have led to the identification of a leukemic stem cell (LSC) population in patients with acute myelogenous leukemia (AML). LSCs are sufficient to perpetuate human leukemic cell growth in long-term culture assays and in the murine NOD/SCID model system. As a consequence of these data, it has been proposed that LSCs are central to the pathogenesis of human myeloid leukemia in vivo. Therefore, the primary objective of this application is to define novel molecular properties of LSCs and to exploit such properties to induce LSC-specific apoptosis. With this goal in mind, our studies have focused on defining unique characteristics of the LSC population. To date, we have shown that primitive AML cells aberrantly regulate several factors related to control of cell death decisions. Further, we have developed a model system in which primary AML cells are induced to undergo apoptosis, but normal cells are spared. Thus, we hypothesize that by targeting specific molecular events it will be possible to preferentially induce apoptosis in the LSC population. This hypothesis will be examined through experiments designed to: 1) characterize the molecular basis of apoptosis in primary AML cells, 2) expand strategies for preferential induction of LSC apoptosis, and 3) use molecular genetic strategies to define critical apoptosis control genes that function in LSCs. Collectively, these efforts will advance our understanding of basic mechanisms that underlie leukemic transformation and will improve strategies for the preferential ablation of LSCs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090446-02
Application #
6621147
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
2002-01-16
Project End
2003-08-31
Budget Start
2003-01-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$257,744
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Jordan, Craig T (2008) Can we finally target the leukemic stem cells? Best Pract Res Clin Haematol 21:615-20
Hassane, Duane C; Guzman, Monica L; Corbett, Cheryl et al. (2008) Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood 111:5654-62
Jordan, Craig T (2007) The leukemic stem cell. Best Pract Res Clin Haematol 20:13-8
Guzman, Monica L; Li, Xiaojie; Corbett, Cheryl A et al. (2007) Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood 110:4436-44
Guzman, Monica L; Rossi, Randall M; Neelakantan, Sundar et al. (2007) An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110:4427-35
Jordan, Craig T; Guzman, Monica L; Noble, Mark (2006) Cancer stem cells. N Engl J Med 355:1253-61
Klebanov, Lev; Jordan, Craig; Yakovlev, Andrei (2006) A new type of stochastic dependence revealed in gene expression data. Stat Appl Genet Mol Biol 5:Article7
Guzman, Monica L; Rossi, Randall M; Karnischky, Lilliana et al. (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105:4163-9
Topisirovic, Ivan; Kentsis, Alex; Perez, Jacqueline M et al. (2005) Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels. Mol Cell Biol 25:1100-12
Guzman, Monica L; Jordan, Craig T (2004) Considerations for targeting malignant stem cells in leukemia. Cancer Control 11:97-104

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