CELL CYCLE SPECIFIC CONTROL OF CELLULAR DIFFERENTIATION

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These studies investigate the regulation of cellular differentiation. The specific primary objectives are to determine: (1)\the amount of anteceding proliferation needed for differentiation; (2)\the cell cycle specificity of cellular processes regulating differentiation; and (3)\whether a central or diverse cellular regulatory process(es) effects different courses of differentiation in a precursor cell. The cell system to be used is the HL-60 human promyelocytic leukemia cell line. Subject to different inducers, HL-60 differentiates along either the myeloid or monocytic pathways. The cell-cycle kinetics and the kinetics of differentiation effected by different inducers will be determined using multiparameter flow cytometric analysis. The cell-cycle specificity of regulatory processes committing this precursor cell to myeloid or monocytic pathways of differentiation will be determined using synchronized cells. The primary scientific questions addressed are: (1)\how much proliferative activity precedes cellular differentiation; (2)\what cellular processes in the proliferative cell cycle are implicated with a regulatory role for effecting differentiation; and (3)\does the same or different cellular-regulatory process(es) govern differentiation along different pathways? These studies directed at understanding the cellular-regulatory mechanism of differentiation are of particular relevance to the pathology of hematological neoplasms. The cellular defect seminal to leukemogenesis is attributable to a pathological differentiative process. The studies should increase the understanding of that pathology and hopefully promote insight into new means of more effective clinical management of such diseases. Of relevance to this is the utilization of these studies of agents which modulate cellular differentiation. Understanding the cellular response to such agents may lead to treatment protocols utilizing these or related compounds. (N)