Mechanisms that uncouple growth and differentiation in myeloid leukemia cells: restoration of requirement for normal growth-inducing protein without restoring induction of differentiation-inducing protein.

Abstract

There are different macrophage-and granulocyte-inducing (MGI) proteins. Normal myeloid precursors are induced to multiply by one form (MGI-1) and to differentiate by another form (MGI-2). There are clones of myeloid leukemia cells that no longer require MGI-1 for growth but can still be induced to differentiate by After induction of differentiation in these leukemia cells by adding MGI-2 or inducing endogenous production of MGI-2 'by lipopolysaccharide, the differentiating leukemia cells, like normal cells, again required MGI-i for growth. This growth requirement for MGI-1 could not be substituted for by adding other protein growthifactors such as epidermal, fibroblast, or nerve growth factor or insulin. Induction of ,differentiation in these leukemia cells by dexamethasone, arabinonucleoside (cytosine arabinoside), or methotrexate instead ofby MGI-2, did not restore the requirement of MGI-1 for growth. Mutant myeloid leukemia cells that could not be induced to differentiate by MGI-2 also did not show this restoration of the requirement of MGI-1 for growth. MGI-1 in normal cells induced cell growth and also induced MGI-2, so that the cells could then differentiate by the endogenously produced MGI-2. However, MGI-1 did not induce production of MGI-2 in the leukemia cells, ,even though they again required MGI-1 for growth, so that there was no induction of differentiation after adding MGI-1. This lack of induction of differentiation-inducing protein by growth-inducing protein has thus identified an effective mechanism for uncoupling of growth and differentiation in malignant cells.Growth (multiplication) and differentiation of normal myeloid cells are controlled by a family ofmacrophage.-and granulocyteinducing (MGI) proteins (1-3). Some of these proteins induce cell growth and others induce differentiation. Those that induce growth, which we now call MGI-i (3-5), include forms that can induce formation of macrophage colonies (MGI-iM) (4, 6, 7), granulocyte colonies (MGI-IG).(4, 6), or both types of colonies (MGI-IGM) (8-10). MGI-i, which is also required for normal cell viability (2, 3), has previously been referred to as mashran gm (11), colony-stimulating factor (12), colony-stimulating activity (13), and MGI (8). The other main type of MGI, which we now call MGI-2 (3-5, 14), induces differentiation ofmyeloid cells without inducing colony formation. This differentiationinducing protein (15) has also been referred to as MGI (16), D factor (17,18) and . We have also found that the growth-inducing protein MGI-i can induce production in normal myeloid cells of the differentiation-inducing protein 14). This induction of MGI-2 by MGI-i can then serve as a regulatory mechanism to ensure the coupling of-growth and -differentiation that occurs in normal cells.There are clones of myeloid leukemia cells that, unlike normal myeloid precursors, are not dependent on MGI-1 for cell viability and growth but can still be induced to differentiate by MGI-2 to mature macrophages or granulocytes (1-4). These mature cells ...

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