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

作者：Rumi Elisa^*; Pietra Daniela; Guglielmelli Paola; Bordoni Roberta; Casetti Ilaria; Milanesi Chiara; Sant' Antonio Emanuela; Ferretti Virginia; Pancrazzi Alessandro; Rotunno Giada; Severgnini Marco; Pietrelli Alessandro; Astori Cesare; Fugazza Elena; Pascutto Cristiana; Boveri Emanuela; Passamonti Francesco; De Bellis Gianluca; Vannucchi Alessandro; Cazzola Mario

来源：Blood, 2013, 121(21): 4388-4395.

DOI：10.1182/blood-2013-02-486050

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.

• 出版日期2013-5-23