title: MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort.
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.
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bench
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.forename: David
authors.initials: D
authors.lastname: Bareford
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilkins
authors.forename: John T
authors.initials: JT
authors.lastname: Reilly
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hasselbalch
authors.forename: Richard
authors.initials: R
authors.lastname: Bowman
authors.forename: Keith
authors.initials: K
authors.lastname: Wheatley
authors.forename: Georgina
authors.initials: G
authors.lastname: Buck
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D015331:Cohort Studies; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000097:blood / Q000235:genetics*; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics; D055728:Primary Myelofibrosis / Q000097:blood / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D012189:Retrospective Studies; D013920:Thrombocythemia, Essential / Q000097:blood / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2