MPLmutations in myeloproliferative disorders: analysis of the PT-1 cohort

Activating mutations of MPLexon 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 MPLmutations 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. MPLmutations were identified in 8.5% of JAK2 V617F−patients and a single V617F+patient. Patients carrying the W515Kallele had a significantly higher allele burden than did those with the W515Lallele, suggesting a functional difference between the 2 variants. Compared with V617F+ET patients, those with MPLmutations 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 MPLmutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. MPLmutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.