Coupling of growth and differentiation in normal myeloid precursors and the breakdown of this coupling in leukemia.

Normal myeloid precursors are dependent on the macrophage and granulocyte growth-inducing protein MGI-1 for cell viability and multiplication. MGI-1 also induces production of the differentiation-inducing protein MGI-2, and this induction of a differentiation-inducing protein by a growth-inducing protein provides a mechanism for the normal coupling of growth and differentiation. It is shown that this induction of MGI-2 by MGI-1 occurs in the myeloid precursors and not in some other cells in the normal bone marrow, that the induced MGI-2 can be detected 6 h after the addition of MGI-1, and that MGI-2 can be induced in these cells by purified MGI-1. There are clones of myeloid leukemic cells that no longer require MGI-1 for cell viability and multiplication, but in which this requirement for MGI-1 can be restored after induction of differentiation by MGI-2. A similar concentration of MGI-1 was required for the optimum induction of growth in these differentiating leukemic cells and in normal myeloid precursors. In the presence of MGI-1 these differentiating leukemic cells multiplied and then lost their differentiation-associated properties. In contrast to normal myeloid cells, MGI-1 did not induce MGI-2 in the MGI-1 requiring differentiating myeloid leukemic cells. This lack of induction of MGI-2 by MGI-1 occurred in cells cultured in serum-containing or serum-free-medium, and can explain the loss of differentiation-associated properties. The results indicate that there has been a genetic breakdown of the normal coupling mechanism between growth and differentiation in these leukemic cells so that MGI-1 can no longer induce MGI-2.