title: Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms.
abstract: We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)-mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy. elisarumi@hotmail.com
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Bordoni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Casetti
authors.forename: Chiara
authors.initials: C
authors.lastname: Milanesi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Sant'Antonio
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferretti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pancrazzi
authors.forename: Giada
authors.initials: G
authors.lastname: Rotunno
authors.forename: Marco
authors.initials: M
authors.lastname: Severgnini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pietrelli
authors.forename: Cesare
authors.initials: C
authors.lastname: Astori
authors.forename: Elena
authors.initials: E
authors.lastname: Fugazza
authors.forename: Cristiana
authors.initials: C
authors.lastname: Pascutto
authors.forename: Emanuela
authors.initials: E
authors.lastname: Boveri
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Bellis
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vannucchi
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000473:pathology / Q000502:physiology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D005355:Fibrosis; D018628:Gene Dosage / Q000235:genetics*; D006098:Granulocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D015994:Incidence; D053614:Janus Kinase 2 / Q000235:genetics; D016015:Logistic Models; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D055815:Young Adult
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2