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‐I for cell viability and multiplication. MGI‐I 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‐I 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‐I, and that MGI‐2 can be induced in these cells by purified MGI‐I. There are clones of myeloid leukemic cells that no longer require MGI‐I for cell viability and multiplication, but in which this requirement for MGI‐I can be restored after induction of differentiation by MGI‐2. A similar concentration of MGI‐I was required for the optimum induction of growth in these differentiating leukemic cells and in normal myeloid precursors. In the presence of MGI‐I these differentiating leukemic cells multiplied and then lost their differentiation‐associated properties. In contrast to normal myeloid cells, MGI‐I did not induce MGI‐2 in the MGI‐I requiring differentiating myeloid leukemic cells. This lack of induction of MGI‐2 by MGI‐I 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‐I can no longer induce MGI‐2.