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Protein kinase C mediates mutant N-Ras-induced developmental abnormalities in normal human erythroid cells

Darley, Richard Lawrence, Pearn, Lorna, Omidvar, Nader, Sweeney, Marion Carol, Fisher, Janet, Phillips, Sarah, Hoy, Terence George and Burnett, Alan Kenneth 2002. Protein kinase C mediates mutant N-Ras-induced developmental abnormalities in normal human erythroid cells. Blood 100 (12) , pp. 4185-92. 10.1182/blood-2002-05-1358

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Abstract

RAS mutations are one of the most frequent molecular abnormalities associated with myeloid leukemia and preleukemia, yet there is a poor understanding of how they contribute to the pathogenesis of these conditions. Here, we describe the consequences of ectopic mutant N-Ras (N-Ras*) expression on normal human erythropoiesis. We show that during early (erythropoietin [EPO]-independent) erythropoiesis, N-Ras* promoted the amplification of a phenotypically primitive but functionally defective subpopulation of CD34(+) erythroblasts. N-Ras* also up-regulated the expression of megakaryocyte antigens on human erythroblasts. Although early erythroblasts expressing N-Ras* were able to respond to erythropoietin and generate mature progeny, this occurred with greatly reduced efficiency, probably explaining the poor colony growth characteristics of these cells. We further report that this oncogene promoted the expression and activation of protein kinase C (PKC) and that the effects of N-Ras* on erythropoiesis could be abrogated or attenuated by inhibition of PKC. Similarly, the effects of this oncogene could be partially mimicked by treatment with PKC agonist. Together, these data suggest that expression of N-Ras* is able to subvert the normal developmental cues that regulate erythropoiesis by activating PKC. This gives rise to phenotypic and functional abnormalities commonly observed in preleukemia, suggesting a direct link between RAS mutations and the pathogenesis of preleukemia.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society of Hematology
ISSN: 15280020
Related URLs:
Last Modified: 25 Jun 2017 01:31
URI: http://orca-mwe.cf.ac.uk/id/eprint/156

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