Retinoic acid and its analogs (retinoids) enhance normal human muyelopoiesis and erythropoiesis, and inhibit leukemic blast cell clonal proliferation and induce differentiation of leukemic blast cells in vitro. The phenotypic abnormality of human acute myelogenous leukemia is the inability of the leukemic cells to differentiate to functional, non- dividing cells. One approach to the therapy of leukemia is the induction of differentiation of the neoplastic cells. A number of new retinoids have been recently synthesized; some of these compounds are 10-100 fold more potent than all-trans retinoic acid in several non-hematopoietic assays. We will test the potency of new retinoids on clonal growth and induction of differentiation of normal and neoplastic human myeloid progenitor cells in vitro. Agents that appear to be effective in vitro will be tested against leukemic cells in vivo in the murine subcapsular renal assay and in nude mice. 2. The mechanism of action of retinoids is not understood. Recently, the retinoic acid receptor (RAR) cDNA has been isolated. We will use the RAR cDNA in an expression vector in combination with RAR antibodies and RAR protein as tools to study the biological role RAR has in normal and neoplastic hematopoietic cells. 3. We shall isolate and study the gene(s) that encodes for novel protein(s) made by T-lymphocytes which induce differentiation of leukemic cells. The gene(s) shall be isolated by a unique expression system. Such factor(s) will be very important for studying the regulation of hematopoiesis and their implication for possibly treating some leukemias is clear. 4. We shall determine the clinical significance of ras mutations in leukemia and preleukkemia. This study will be possible because of the marriage of three recent advances: 1) polymerase chain reaction; 2) Taq polymerase; 3) ability to isolate useful DNA from formaldehyde-fixed, paraffin embedded bone marrow specimens. We will examine for ras mutations in the DNA from several 1000 samples for which we already have the clinical data of the patients. This knowledge may give insights into the pathogenesis of some leukemias and may allow better sub-classification of leukemias and preleukemias. As a whole, the studies will provide an understanding of both the process of normal myeloid differentiation and the defect in differentiation of blast cells in some leukemias. Our findings may have clinical applications for certain leukemias.
Showing the most recent 10 out of 83 publications
