Understanding the processes that regulate the developmental program of normal stem cells and how aberrations in this program initiate leukemic proliferation remain a major challenge in biology. Progress to address these major questions in the human hematopoietic system has been hampered, until recently, by the lack of in vivo assays for normal and leukemic stem cells. The only way to conclusively assay stem cells is to follow their repopulating capacity. The recent development of methods to transplant human hematopoietic cells into immune-deficient mice provides an important approach to characterize stem cells and to develop animal models for hematopoietic diseases including leukemia. The development of an in vivo model that replicates many aspects of human AML and allows the identification of a novel leukemic stem cell (termed the SCID-Leukemia Initiating Cell, SL-IC) based on the ability of that cell to initiate AML in NOD/SCID mice provides the foundation of an assay to define the biological and molecular properties of such new leukemic stem cells. The major long-term objectives of my research program are to further characterize human leukemic stem cells. The research project proposed here will focus on three objectives: 1) determine the existence of an heterogeneity at the leukemic stem cell level (both Lin-CD34+ and Lin-CD341o/- subfractions have leukemic stem cell properties); 2) evaluate the biological properties of the leukemic stem cell pool (i.e., self-renewal, proliferation and differentiation capacities, response to cytokines and/or stromal cell environment); 3) to study the gene expression pattern of six regulatory molecules (AML1, PU.1, GATA- 1, Hox A5, Hox B4 and SCL/tal-1), known to be involved in the early stage of hematopoietic development and/or in the physiopathology of leukemia, before and after induction of differentiation of the leukemic stem cell fraction. The information obtained from these studies will gave us a more complete understanding of the nature of the leukemic stem cells, their biological properties, and the early molecular factors involved in the maintenance and/or differentiation of such leukemic stem cells. Furthermore, the knowledge gained about leukemic stem cells will allow us to devise new therapeutic strategies such as cell purging strategy, gene suicide therapy, antisense therapy and others, targeted specifically to the leukemic stem cell pool.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Mufson, R Allan
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Coriell Institute for Medical Research
United States
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