Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms.

Elisa Rumi, Daniela Pietra, Paola Guglielmelli, Roberta Bordoni, Ilaria Casetti, Chiara Milanesi, Emanuela Sant'Antonio, Virginia Ferretti, Alessandro Pancrazzi, Giada Rotunno, Marco Severgnini, Alessandro Pietrelli, Cesare Astori, Elena Fugazza, Cristiana Pascutto, Emanuela Boveri, Francesco Passamonti, Gianluca De Bellis, Alessandro Vannucchi, Mario CazzolaItaliana per la Ricerca sul Cancro Gruppo Associazione Italiana per la Ricerca sul Cancro Gruppo, Malattie Mieloproliferative Italiano Malattie Mieloproliferative

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4388-4395
Number of pages8
JournalBlood
Volume121
Issue number21
DOIs
Publication statusPublished - May 23 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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