Retinoic-acid-induced modulation of c-myc not dependent on its continued presence: possible role in pre-commitment...

Induced differentiation of HL-60 human promyelocytic cells along the myeloid or monocytic lineages has been previously shown to involve an intermediate regulatory state, the pre-commitment state. Pre-commitment cells have completed the early events in the processes leading ultimately to terminal differentiation and require only an abbreviated subsequent exposure to inducer for onset of terminal differentiation. The pre-commitment state has 2 properties relevant to the present communication: (1) when induced by retinoic acid (RA), it has a characteristic duration following removal of the RA; and (2) it can also be induced by a pulse exposure to hydroxyurea. In the present studies, it was observed that after exposure of HL-60 human promyelocytic leukemia cells to RA for 24 hr (ca. one division cycle) their levels of c-myc RNA were elevated. The c-myc RNA level then remained elevated for several subsequent division cycles despite the removal of retinoic acid. Thus, retinoic acid induced a change in HL-60 c-myc RNA levels which was sustained regardless of the continued presence or absence of RA. The elevation, decreasing to control levels 3 division cycles after termination of the pulse exposure, paralleled the known duration of the pre-commitment memory state. Furthermore, a pulse exposure of HL-60 cells to a subcytotoxic dose of hydroxyurea, which is also known to induce a pre-commitment state, also induced an elevation of c-myc RNA levels. The observed changes in c-myc levels were not common to all oncogenes. C-fos responded differently to the retinoic acid treatment. Furthermore, although hydroxyurea affected c-myc levels, it did not alter c-fos levels. Most significantly, the present results suggest a cellular function for the c-myc gene product, which is derivation of the pre-commitment state.