MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort

• Published in: Blood 2008-07, Vol.112 (1), p.141-149
• Main Authors: Beer, Philip A., Campbell, Peter J., Scott, Linda M., Bench, Anthony J., Erber, Wendy N., Bareford, David, Wilkins, Bridget S., Reilly, John T., Hasselbalch, Hans C., Bowman, Richard, Wheatley, Keith, Buck, Georgina, Harrison, Claire N., Green, Anthony R.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alleles; Base Sequence; Biological and medical sciences; Cohort Studies; DNA, Complementary - genetics; Exons; Female; Hematologic and hematopoietic diseases; Humans; Janus Kinase 2 - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Mutation; Myeloproliferative Disorders - blood; Myeloproliferative Disorders - genetics; Polycythemia Vera - blood; Polycythemia Vera - genetics; Primary Myelofibrosis - blood; Primary Myelofibrosis - genetics; Prognosis; Prospective Studies; Receptors, Thrombopoietin - genetics; Retrospective Studies; Thrombocythemia, Essential - blood; Thrombocythemia, Essential - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-01-131664

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 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction 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− patients and a single V617F+ patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F+ 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 with V617F− patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.