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In this research project, we plan to quantitatively assess somatic mutations of JAK2 and MPL in patients with Ph-negative myeloproliferative neoplasms. Our working hypothesis is that there is a relationship not only between mutation type and clinical phenotype, but also between mutant allele burden and risk of hematologic transformation. In order to study the clonal evolution of myeloproliferative neoplasms in patients with JAK2 and/or MPL mutations, we will use ultra-deep sequencing, which allows the analysis of phylogenetic structures, and therefore the relationships between dominant clone ad subclones. In addition, using a genome-wide human SNP array, we will try to define chromosomal regions characterized by loss of heterozygosity (LOH) and or copy number variation, and to identify genes potentially associated with disease progression, in particular with evolution into acute myeloid leukemia.
In addition, we will study the genetic predisposition to acquiring somatic mutations of JAK2 and MPL in familial myeloproliferative neoplasms. Recent studies indicate that the unique JAK2 mutation is preferentially found within a particular JAK2 haplotype, suggesting a strong interaction between germline genetics and somatic mutations at this locus. To characterize this interaction, we will study our pedigrees with at least two relatives affected by myeloproliferative neoplasms by performing a genome-wide linkage analysis through a genome-wide human SNP array. Finally, we will participate in clinical trials on the use of innovative drugs for treatment of myeloproliferative neoplasms.
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