Synchrony of gene expression and the differentiation of myeloid leukemic cells: reversion from constitutive to inducible protein synthesis.

There are mutant myeloid leukemic cells that cannot be induced to differentiate in serum-free culture medium, or medium with calf serum by the macrophage and granulocyte differentiation-inducing protein (MGI-2) that induces differentiation in normal myeloid cells. These mutants can be induced to differentiate by MGI-2 in medium with mouse serum. The mechanism of this induction of differentiation has been analysed by using two-dimensional gel electrophoresis to study changes in the synthesis of cytoplasmic proteins. In calf serum, 46 of the protein changes that were induced by MGI-2 in normally differentiating cells were constitutive in the differentiation-defective mutant cells. Treatment with mouse serum reverted 13 of these proteins from the constitutive to the non-constitutive state. This reversion was associated with a gain of inducibility for various differentiation-associated properties, so that 23 proteins were induced by MGI-2 for the same type of change as in normal differentiation. A normal developmental program requires synchrony of gene expression. The existence of constitutive instead of inducible gene expression can produce asynchrony in this program and thus produce blocks in differentiation. The results indicate that it is possible to treat these mutant cells so as to induce the reversion of specific proteins from the constitutive to the non-constitutive state, and that this can then restore the synchrony required for induction of differentiation. It is suggested that this mechanism may also allow induction of differentiation in other types of differentiation-defective cells.