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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2248-2256.
Prepublished online as a Blood First Edition Paper on June 8, 2006; DOI 10.1182/blood-2006-02-002188.
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Submitted February 7, 2006
Accepted May 30, 2006
A critical role for the transcription factor Scl in platelet production during stress thrombopoiesis
Matthew P McCormack, Mark A Hall, Simone M Schoenwaelder, Quan Zhao, Sarah Ellis, Julia A Prentice, Ashleigh J Clarke, Nicholas J Slater, Jessica M Salmon, Shaun P Jackson, Stephen M Jane, and David J Curtis*
Royal Melbourne Hospital, Melbourne Health Research Directorate, Australia
St Jude Children's Research Hospital, Memphis, TN, USA
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
Microscopy Imaging Facility, Peter MacCallum Research Institute, East Melbourne, Australia
* Corresponding author; email: dcurtis{at}wehi.edu.au.
The generation of platelets from megakaryoctes in the steady state is regulated by a variety of cytokines and transcription factors, including thrombopoietin (TPO), GATA-1 and NF-E2. Less is known about platelet production in the setting of stress thrombopoiesis, a pivotal event in the context of cytotoxic chemotherapy. Here we show in mice that the transcription factor Scl is critical for platelet production after chemotherapy, and in thrombopoiesis induced by administration of thrombopoietin (TPO). Megakaryocytes from these mice showed appropriate increases in number and ploidy, but failed to shed platelets. Ultrastructural examination of Scl-null megakaryocytes revealed a disorganised demarcation membrane and reduction in platelet granules. Quantitative real-time PCR showed that Scl-null platelets lacked NF-E2, and chromatin immunoprecipitation analysis demonstrated Scl binding to the NF-E2 promoter in the human megakaryoblastic cell line Meg-01, along with its binding partners E47, Lmo2 and the cofactors Ldb1 and GATA-2. These findings suggest that Scl acts upstream of NF-E2 expression to control megakaryocyte development and platelet release in settings of thrombopoietic stress.
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