SELF-RENEWAL IN LEUKEMIC STEM CELLS

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DESCRIPTION (provided by applicant): Our long-term objectives are to advance the understanding of the molecular mechanism(s) that govern the self-renewal property of leukemic stem cells (LSCs). LSCs are cells that can give rise to leukemia in transplant models, and therefore have self-renewal properties. It is hypothesized that these cells are not targeted under current chemotherapy regimens and therefore account for drug resistance and leukemia relapse. Identifying genes or signaling pathways involved in the self-renewal of LSCs will likely promote the development of more effective treatments for leukemia and other cancers. Bmi-1 is a key element involved in LSC self-renewal, and is aberrantly upregulated in LSCs. The underlying cause(s) for deregulation of Bmi-1 in LSCs remain unknown. We have discovered that SALL4, a newly identified pluripotency factor and a novel oncogene, is aberrantly expressed in human acute myeloid leukemia (AML). Transgenic mice that mimic this aberrant expression of SALL4B, one of the SALL4 isoforms, develop AML.8 Further studies on these SALL4B mice have led to the identification and characterization of LSCs in the SALL4B-induced AML mouse model. Parallel to gain-of-function studies, knockdown of SALL4 expression in leukemic cell lines triggers cell apoptosis and growth arrest. While upregulation of Bmi-1 is found in the SALL4B-induced LSCs, downregulation of SALL4 leads to decreased expression of Bmi-1. Restoring Bmi-1 expression in SALL4 knockdown leukemic cell lines rescues the apoptotic phenotype. More detailed studies have demonstrates that Bmi-1 is a direct target of SALL4 in bone marrow cells. Based on these findings, we hypothesize that deregulation of SALL4B plays a key role in promoting self-renewal of LSCs by activation of Bmi-1. To prove this hypothesis, I propose to 1) Determine the functional role(s) of SALL4 in self-renewal of normal hematopoietic stem cell (HSCs) and LSCs; and 2) Define the mechanism of SALL4 enhancement of self-renewal of HSCs and LSCs with a focus on its up-regulation of Bmi-1. These two groups of experiments will serve to better understand the critical mechanism(s) in leukemogenesis, and potentially develop novel strategies to combat leukemia. PUBLIC HEALTH RELEVANCE: In United States, there are 33,000 new cases of leukemia (blood cancer) with a death rate of 23,000 every year. Despite chemotherapy and bone marrow transplantation, most leukemia relapses and has a high-mortality rate. One recent approach to decrease the incidence of relapse involves targeting "leukemic stem cell (LSC)", and we propose to test the functional role of a novel oncogene SALL4 in LSCs and its potential usage in treating leukemia.