HUMAN-MOUSE CHIMERA ASSAYS

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Lymphohematopoietic stem/progenitor cell biology is the long-term interest of Dr. Civin's laboratory. In addition, as clinical hematologist- oncologists, we desire to make direct application of our work to clinical treatment, especially stem/progenitor cell transplantation. Further understanding of the biology of human stem/progenitor cells is essential for many basic questions with clinical relevance, since these are the cells of origin of severe aplastic anemias (SAA), myelodysplastic syndromes (MDS) and leukemias, and because purified stem/progenitor cells are powerful therapeutic tools, especially (though not exclusively) for hematologic disorders. Development for feasible laboratory assays for human lymphohematopoietic stem cells (HSC) is important for basic understanding of hematopoiesis and for clinical BMT. New assays for HSC must be validated by clinical transplantation of candidate HSC, since human transplantation is currently the only way to definitively prove the presence of human HSC in the graft. Specific Aim 1 of Project 2 will extensively characterize "SCID repopulating cells" (SRC), the normal human hematopoietic cells which engraft in irradiated immunodeficient mice, with respect to immunophenotype. SRC will be compared with normal human and murine HSC. Specific Aim 2 will determine the effects of short-term ex vivo culture, an important approach in hematopoietic transplantation, on SRC. Specific Aim 3 will assess the use of SRC assays in cases of SAA, MDS, leukemias, and pediatric solid tumors. This may allow better definition of cancer stem cells, the cells which cause relapse. The laboratory investigation of normal and malignant stem/progenitor cell biology in Project 2 is central to the entire Program Project.