Bone marrow transplantation (BMT) offers great promise for cure of most hematologic malignancies, a number of solid cancers, and a variety of fatal non-malignant disorders. Nevertheless, only a minority of patients with diseases potentially curable by BMT are indeed cured, since many are not eligible for BMT a significant number who are transplanted die of toxicity or disease recurrence. The ability to isolate and expand lymphohematopoietic stem cells (HSC) will improve both the availability and outcome of BMT. Use of purified HSC may avoid histocompatibility problems in allogeneic BMT, as well as improve autologous BMT, for cancer and certain other disease, and for gene therapy. The overall goal of this Program Project (C. Civin, PI) is to study normal HSC clinically and their best surrogates in the laboratory, and to utilize HSC in human transplantation. Clinical and laboratory studies will proceed in parallel; insights generated in one sphere will translate to the other. Project 1 (Jones) will conduct pre-clinical experiments and clinical trials of stem-progenitor cell transplantation for patients with myelodysplastic syndromes (MDS), pediatric solid tumors, severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), and autoimmune diseases. In utero transplantation will be investigated for patients with inherited diseases. Project 2 (Civin) will use the human-immunodeficient mouse assay for stem/progenitor cells to answer questions arising from the above clinical trials, to assess purification of candidate human HSC, to test the ex vivo expansion of the engrafting capacity of cord blood stem/progenitor cells, and to measure normal engrafting cells in SAA and cancer stem cells in PNH, MDS, acute leukemias and pediatric solid tumors. Project 3 (Sharkis) will study the key hematopoietic marker, CD34. CD34 null and knock-out mice will be used to determine whether CD34 gene function is required for stem cell self-renewal, proliferation, and/or differentiation. Simultaneously, Project 3 will determine the molecular components of CD34 signal transduction. Project 4 (Small) will concentrate on the FLT3/STK1 receptor. Cis-and trans-regulatory factors important to its expression in normal hematopoiesis and leukemia will be studied. The potential functional role of the FLT3/STK1 molecule in leukemia will be modeled with a constitutively activated receptor.
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