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

Blood. 2013 May 23;121(21):4388-95. doi: 10.1182/blood-2013-02-486050. Epub 2013 Apr 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Bone Marrow / pathology
  • Bone Marrow / physiology
  • Chromosomes, Human, Pair 1 / genetics*
  • Female
  • Fibrosis
  • Gene Dosage / genetics*
  • Granulocytes / pathology
  • Granulocytes / physiology
  • Humans
  • Incidence
  • Janus Kinase 2 / genetics
  • Logistic Models
  • Loss of Heterozygosity / genetics*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / mortality
  • Myeloproliferative Disorders / pathology
  • Receptors, Thrombopoietin / genetics*
  • Young Adult

Substances

  • Receptors, Thrombopoietin
  • MPL protein, human
  • JAK2 protein, human
  • Janus Kinase 2