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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4461-4469. Prepublished online as a Blood First Edition Paper on January 25, 2007; DOI 10.1182/blood-2006-09-047217. This Article Full Text (PDF) All Versions of this Article: blood-2006-09-047217v1 109/10/4461    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pearn, L. Articles by Darley, R. L Search for Related Content PubMed PubMed Citation Articles by Pearn, L. Articles by Darley, R. L Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 15, 2006 Accepted January 3, 2007 The role of PKC and PDK1 in monocyte lineage specification by Ras Lorna Pearn, Janet Fisher, Alan K Burnett, and Richard L Darley* Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom Department of Pathology, School of Medicine, Cardiff University, Cardiff, United Kingdom * Corresponding author; email: darley{at}cf.ac.uk. Though hyperactivation of Ras is a common feature of myeloid malignancy, its role in subverting haematopoiesis is unclear. We have examined the influence of Ras on normal human uncommitted myeloid subsets and show that expression of this oncogene strongly favours monocyte lineage selection in bipotential granulocyte/macrophage progenitors while inhibiting colony formation in other uncommitted subsets. Ras also promoted monocytic differentiation, but not the proliferation of these cells. The mechanism through which Ras drives monocyte lineage selection was dependent on PKC activity and Ras was found to promote the expression, membrane translocation and phosphorylation of conventional and novel PKC isoforms. We further show that Ras promoted the expression of the AGC kinase master regulator, PDK1, which maintains the stability and activity of PKC isoforms. Consistent with this, overexpression of PDK1 itself, promoted monocyte colony formation and translocation of PKC. Overexpression of PDK1 was found to be a common feature of acute myeloid leukaemia (45% of patients) and was closely associated with hyperphosphorylation of PKC. These data demonstrate that Ras is able to promote monocyte lineage selection via PKC and show for the first time the involvement of the kinase master regulator, PDK1, in both lineage specification and in human leukaemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Pedersen-Bjergaard, M. T. Andersen, and M. K. Andersen Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia Hematology, January 1, 2007; 2007(1): 392 - 397. [Abstract] [Full Text] [PDF]

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