Hydroxyurea induces precommitment during retinoic induced HL-60 terminal myeloid differentiation: Possible involvement of gene amplification

Abstract

Control of terminal cell differentiation was studied in the HL-60 human promyelocytic leukemia cell line. Retinoic acid is known to induce myeloid differentiation associated with GO arrest in these cells. In this case, onset of terminal differentiation occurs after an exposure period corresponding to two division cycles. This is preceded by acquisition of a precommitment memory state occurring by one division cycle. Cells in precommitment undergo accelerated onset of terminal differentiation upon reexposure to inducer. The present report shows that the precommitment state can be induced by a pulse exposure to hydroxyurea. While the hydroxyurea exposure does not itself induce terminal differentiation, the treated cells undergo accelerated onset of phenotypic differentiation and GO arrest upon exposure to retinoic acid. Thus a perturbation of S-phase specific cellular metabolism induces the early precommitment regulatory state in the course of induced HL-60 terminal myeloid differentiation. The results support a model in which initiation of a cellular program of terminal differentiation depends on an S-phase specific event associated with replication of cellular DNA and possibly involving gene amplification. Significantly, the results indicate that a conventional chemotherapeutic agent such as hydroxyurea can synergistically interact with a differentiation inducing agent such as retinoic acid. This indicates the significance of investigating the interaction between conventional S-phase specific chemotherapeutic agents and differentiation inducing agents as a potential treatment modality.