PRE-COMMITMENT REGULATION OF CELL DIFFERENTIATION

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These studies investigate the control of cell differentiation in an in vitro uncommitted human precursor cell. The experimental system is the HL-60 human promyelocytic leukemia cell line, a differentially bipotent cell which undergoes either myeloid or monocytic terminal cell differentiation. Previous studies on myeloid differentiation showed that cellular response to an induction signal involved two intermediate states, pre-commitment and commitment, occurring before phenotypic terminal differentiation of the cells. Commitment is the point after which removal of the inducing signal does not prevent subsequent cell differentiation. The existence of such a point has been found in other experimental systems, too. Pre-commitment, in contrast, is an earlier state where removal of the inducer results in cells which fail to subsequently phenotypically differentiate or growth arrest. Pre-commitment cells require only an abbreviated subsequent exposure to inducer to phenotypically differentiate and growth arrest. The pre-commitment state is labile and associated with characteristic changes in nuclear envelope structure and cytoplasmic proteins. The data suggest a model in which pre-commitment is effectively a fail-safe state. In response to an inducing signal, a precursor cell is first driven to this state. If it receives a subsequent signal, it is driven to commitment. If not, it reverts to its initial naive state. The pre-commitment state is thus of significance as an identifiable regulatory state. The object of this research is to detemine if this state is generalizable to the monocytic lineage and to determine the relationship between the myeloid lineage pre-commitment state and the monocytic one. We will determine if cellular progression to the same state of terminal differentiation is due to different inducers involving the same intermediate pre-commitment state, if the pre-commitment regulatory state differentiation is lineage specific, and if the changes in cytoplasmic proteins and/or nuclear membrane structure are associated with the pre-commitment state during myeloid differentiation also common to the course of monocytic differentiation. (M)