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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-05-1358.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4185-4192
NEOPLASIA
Protein kinase C mediates mutant N-Ras-induced developmental
abnormalities in normal human erythroid cells
Richard L. Darley,
Lorna Pearn,
Nader Omidvar,
Marion Sweeney,
Janet Fisher,
Sarah Phillips,
Terry Hoy, and
Alan K. Burnett
From the Leukaemia Research Fund Differentiation Group,
Department of Haematology, University of Wales College of Medicine,
Cardiff, United Kingdom.
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.
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