Journal
BLOOD
Volume 121, Issue 21, Pages 4388-4395Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-02-486050
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Funding
- Associazione Italiana per la Ricerca sul Cancro (Milan, Italy) [1005]
- Fondo per gli investimenti della ricerca di base [RBAP11CZLK]
- Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale [2010NYKNS7]
- Italian Ministry of Health [GR-2010-2312855]
- Italian Society of Experimental Hematology
- Regione Toscana, Programma per la ricerca regionale in materia di salute
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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.
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