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MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort
Philip A Beer1, Peter J Campbell, Linda M Scott
1Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
Abstract:
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.
Insights
Activating MPL exon 10 mutations are found in 8.5% of essential thrombocythemia (ET) or idiopathic myelofibrosis (IMF) patients negative for JAK2 V617F. These mutations do not significantly impact patient prognosis or survival outcomes.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Activating mutations in MPL exon 10 are found in some patients with essential thrombocythemia (ET) or idiopathic myelofibrosis (IMF).
- The prevalence and clinical significance of these MPL mutations remain unclear.
Purpose of the Study:
- To investigate the prevalence and clinical significance of MPL exon 10 mutations in patients with ET or IMF.
- To compare the clinical and pathological features of patients with MPL mutations to those with JAK2 V617F mutations and wild-type JAK2.
Main Methods:
- Retrospective analysis of 200 patients with ET or IMF to identify MPL mutations in granulocyte DNA.
- Genotyping of 776 ET patients using allele-specific polymerase chain reaction in the PT-1 studies.
- Comparison of clinical and laboratory parameters between patient groups.
Main Results:
- Four distinct MPL exon 10 mutations were identified in granulocyte DNA.
- MPL mutations were found in 8.5% of JAK2 V617F-negative ET/IMF patients.
- Patients with MPL mutations showed distinct clinical features, including lower hemoglobin and higher platelet counts, but lacked prognostic significance for survival or adverse events.
Conclusions:
- MPL exon 10 mutations are an uncommon but distinct molecular event in ET/IMF.
- While associated with specific clinical characteristics, MPL mutations do not appear to influence patient prognosis.
- Further research may elucidate the functional differences between MPL W515K and W515L alleles.
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