Normal Differentiation of Myeloid Leukaemic Cells induced by a Differentiation-inducing Protein

Fibach, Eitan; Landau, Tamar; Sachs, Leo

doi:10.1038/newbio237276a0

Cited by 120 publications

(52 citation statements)

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“…This raises the question whether leukemic cells can be reprogramed to regain normal behavior. We found that there are myeloid leukemic cells that can be induced to di erentiate to non dividing mature granulocytes and macrophages by di erent cytokines (Paran et al, 1970;Fibach et al, 1972;Lotem and Sachs, 1977;Shabo et al, 1988;and reviewed in Sachs, 1978and reviewed in Sachs, , 1986and reviewed in Sachs, , 1987aand reviewed in Sachs, ,b, 1995and reviewed in Sachs, , 1996. This showed that these leukemic cells can be reprogramed to behave like non malignant cells.…”

Section: Reprograming Of Gene Expression In Malignant Cells: Control mentioning

confidence: 99%

Cytokine control of developmental programs in normal hematopoiesis and leukemia

2002

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Section: Reprograming Of Gene Expression In Malignant Cells: Control mentioning

confidence: 99%

Cytokine control of developmental programs in normal hematopoiesis and leukemia

2002

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“…This was also the only clone that was induced to differentiate in vitro with the MGI of about 23,000 molecular weight purified from conditioned medium from mouse lungs (36). MGI with molecular weight about 68,000 (12,34,35), purified from fibroblast conditioned medium, induced normal differentiation (7) in MGI+D+ clones of the type that were not induced to differentiate by the MGI of about 23,000 molecular weight. All the clones were also induced to differentiate normally in vitro by unfractionated conditioned medium from mouse lungs.…”

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confidence: 99%

“…We have developed an in vitro system to study the controls that regulate growth and differentiation of normal (1)(2)(3)(4)(5)(6) and leukemic (5-11) myeloid cells. The use of this system has shown that the normal macrophage-and granulocyte-inducing protein (2-4), which we now call MGI (6,12), can induce in vitro normal precursor cells (2)(3)(4)(5)(6)13) and some types of myeloid leukemic cells in mice (7)(8)(9)(10)(11) and humans (5) to undergo complete differentiation to mature macrophages or granulocytes. Mouse myeloid leukemic cell clones have been established that can be grown in culture as myeloblasts to promyelocytes, have a high leukemogenic capacity, and express different genetic blocks in differentiation (8)(9)(10)(11).…”

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confidence: 99%

“…The chambers were made as described (23) (12,34,35); MGI, molecular weight of about 23,000, has been purified from mouse lung conditioned medium (36). The 68,000 molecular weight MGI can induce in vitro the differentiation of MGI+D+ clones such as 9 and 12 to mature macrophages and granulocytes (7). However, the 23 (Fig.…”

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confidence: 99%

“…(27). MGI-Dclones 1 and 6 were from two independently arising myeloid leukemias in SJL/J mice (9,10,14); MGI+D+ clone 7-M12 was derived after mutagenesis from MGI-D-clone 7 (10). The clone 1 used in these experiments differs from the clone 1 used previously (14) in that it now spontaneously has 6.2% Fc rosettes instead of 0.2% Fc rosettes.…”

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In vivo induction of normal differentiation in myeloid leukemia cells

Lotem¹,

Sachs²

1978

Proc. Natl. Acad. Sci. U.S.A.

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MGI+D+, MGI+D-, and MGI-D-mouse myeloid leukemic cells, which genetically differ in their competence to be inducbd to undergo normal cell differentiation in vitro by the normal macrophage-and anulocyte-inducing irotein MGI, were analyzed for their afility to undergo cell differentiation in diffusion chambers in vivo. As after induction by MGI in vitro, MGI+D+ clones were induced for Fc and C3 rosettes, lysozyme, and mature macrophages and granulocytes in normal syngeneic or allogeneic mice. MGI+D-clones were also induced in these mice for all these properties, although in vitro they were not induced by MGI for mature cells. The MGI-D-clones were induced in vivo for C3 and Fc rosettes, lysozyme, and intermediate stages but not for mature cells, whereas none of these properties were induced in these clones by MGI in vitro. Thus, certain types of myeloid leukemic cells differentiate better in vivo, possibly due to the presence of higher effective concentrations of MGI and/or other inducing factors, and MGI+D+ and MGI+D-cells can completely differentiate in vivo to mature cells. In vivo differentiation was inhibited in mice treated with cyclophosphamide. It was also inhibited in various strains of nude mice, except for one MGI+D+ clone, where it was inhibited in C57BL/6 but not in ICR nude mice. This MGI+D+ clone was also the only clone that was induced to differentiate normally in vitro by a 23,000 molecular weight form of purified MGI. The results suggest that different clones respond to different molecular forms of MGI, which may be present in different proportions in some animals, that in vivo differentiation by MGI possibly with other factors may be regulated by cells involved in the immune response, and that this differentiation can be genetically controlled. Differentiation in vivo was enhanced by injection of conditioned medium containing MGI and by inoculation of MGI-roducing cells, including normal granulocytes. This indicates that the induction of normal differentiation of myeloid leukemic cells in vivo can be enhanced by these treatments. We have developed an in vitro system to study the controls that regulate growth and differentiation of normal (1-6) and leukemic (5-11) myeloid cells. The use of this system has shown that the normal macrophage-and granulocyte-inducing protein (2-4), which we now call MGI (6, 12), can induce in vitro normal precursor cells (2-6, 13) and some types of myeloid leukemic cells in mice (7-11) and humans (5) to undergo complete differentiation to mature macrophages or granulocytes. Mouse myeloid leukemic cell clones have been established that can be grown in culture as myeloblasts to promyelocytes, have a high leukemogenic capacity, and express different genetic blocks in differentiation (8-11). Some of these clones (MGI+D+) can be induced in vitro by purified MGI (7) to undergo differentiation to mature macrophages and granulocytes. This differentiation occurs via the normal differentiation sequence of induction of C3 and Fc rosettes (9, 14), C3-and Fc-mediated immu...

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The control of growth and differentiation in normal and leukemic blood cells

Sachs

1990

Cancer

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The establishment of a cell culture system for the clonal development of hematopoietic cells has made it possible to discover the proteins that control growth and differentiation of different hematopoietic cell lineages and the molecular basis of normal and abnormal cell development in blood-forming tissues. A model system with myeloid cells has shown that normal hematopoietic cells require different proteins to induce cell multiplication and cell differentiation, and that a cascade of interactions between proteins determines the correct balance between immature and mature cells in normal development. Gene cloning has shown that there is a family of different genes for these proteins. Normal protein regulators of hematopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation to mature nondividing cells. Genetic abnormalities that give rise to malignancy in these leukemic cells can be bypassed and their effects nullified by inducing differentiation, which stops cells from multiplying. These hematopoietic regulatory proteins are active in culture and in vivo and have been used clinically to correct defects in blood cell development. The results provide new approaches to therapy.

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Normal Differentiation of Myeloid Leukaemic Cells induced by a Differentiation-inducing Protein

Cited by 120 publications

References 10 publications

Cytokine control of developmental programs in normal hematopoiesis and leukemia

Cytokine control of developmental programs in normal hematopoiesis and leukemia

In vivo induction of normal differentiation in myeloid leukemia cells

The control of growth and differentiation in normal and leukemic blood cells

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