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Blood, 1 July 2008, Vol. 112, No. 1, pp. 141-149.
Prepublished online as a Blood First Edition Paper on May 1, 2008; DOI 10.1182/blood-2008-01-131664.
 Previous Article | Next Article 
Submitted January 3, 2008
Accepted April 6, 2008
MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort
Philip A Beer, Peter J Campbell, Linda M Scott, Anthony J Bench, Wendy N Erber, David Bareford, Bridget S Wilkins, John T Reilly, Hans C Hasselbalch, Richard Bowman, Keith Wheatley, Georgina Buck, Claire N Harrison, and Anthony R Green*
Department of Haematology, University of Cambridge, Cambridge, United Kingdom
Wellcome Trust, Wellcome Trust Sanger Institute, Duxford, United Kingdom
Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom
Department of Haematology, Russell's Hall Hospital, Dudley, United Kingdom
Department of Pathology, Royal Victoria Infirmary, Newcastle, United Kingdom
Department of Haematology, Royal Hallamshire Hospital, Sheffield, United Kingdom
Department of Haematology and Pathology, Odense University Hospital, Odense, Denmark
MRC Dunn Nutrition Unit, University of Cambridge, Cambridge, United Kingdom
Birmingham Clinical Trials Unit, Birmingham, United Kingdom
Clinical Trials Service Unit, Oxford, United Kingdom
Department of Haematology, St Thomas's Hospital, London, United Kingdom
* Corresponding author; email: arg1000{at}cam.ac.uk.
Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET) but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet cDNA and identify four different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific PCR was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F-negative patients and a single V617F-positive patient. Patients carrying the W515K allele had a significantly higher allele burden than those with the W515L allele, suggesting a functional difference between the two variants. Compared to V617F-positive ET patients, those with MPL mutations displayed lower hemoglobin and higher platelet levels at diagnosis, higher serum erythropoietin levels, endogenous megakaryocytic but not erythroid colony growth and reduced bone marrow erythroid and overall cellularity. Compared to V617F-negative patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinico-pathological subgroup. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.
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