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Mutant RAS inhibits neutrophil but not macrophage differentiation and allows continued growth of neutrophil precursors

Darley, Richard Lawrence and Burnett, Alan Kenneth 1999. Mutant RAS inhibits neutrophil but not macrophage differentiation and allows continued growth of neutrophil precursors. Experimental Hematology 27 (11) , pp. 1599-1608. 10.1016/S0301-472X(99)00100-9

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Mutational activation of RAS is the most common molecular abnormality in myeloid leukemias. In order to better understand its role in leukemogenesis, we have devised a model based on the multipotent cell line, FDCP-mix. We show that expression of mutant RAS in FDCP-mix strongly inhibits terminal neutrophil differentiation under the influence of G-CSF plus GM-CSF at the metamyelocyte stage, whereas macrophage differentiation was unaffected. In addition, whereas control cultures differentiated and became postmitotic under these conditions, FDCP-mix cells expressing mutant RAS continued to proliferate indefinitely while maintaining a metamyelocytic phenotype. Labeling of these cultures with the fluorescent tracking dye, PKH26, showed that this extended proliferative capacity resulted from continued division of metamyelocytes in the culture. Dissection of the growth factor response of these cells demonstrated that GM-CSF was critical in maintaining proliferation and inhibiting the differentiation of these cells. We further show the block in neutrophil differentiation could be partially overcome by treatment with low-dose Ara C, suggesting that maintenance of cell cycle progression may be partly responsible for the anti-differentiation effect of this oncogene. These findings suggest that activation of RAS is able to specifically inhibit terminal neutrophil differentiation and in so doing promotes continued division of metamyelocyte cells.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Elsevier
ISSN: 0301-472X
Last Modified: 25 Jun 2017 04:41

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