German Clinical Trials Register

Acronym/abbreviation of the study

MAry

URL of the study

No Entry

Brief summary in lay language

Myeloproliferative neoplasms (MPN) are associated with proliferation of various cells in the bone marrow and blood. Several subgroups are included in the group of MPN diseases. Myelofibrosis, essential thrombocythemia, and polycythemia vera (PV) are relevant for this study. Furthermore, we distinguish 2 age groups: young adults (age: 18 to 39 years) and older adults (age: ≥ 40 years). The aim of the study is to determine biomedical correlations by comparative study of larger groups of individuals. We would like to investigate to what extent the different "acquired" mutations can be responsible for inflammatory processes, which then also lead to the above-mentioned disease symptoms, such as thrombosis. In this study, we will investigate differences between the clinical symptoms and the underlying genetic alterations. We will divide patients into the age groups already mentioned (patient group 1: ages 18 and 39 years; patient group 2: patients aged 40 years and older). Differences will be assessed by clinical and laboratory characteristics (the phenotype) as well as the underlying genetics (the genotype) of the patients. The aim of this clinical study is to better understand the influence of genetic changes on the clinical course of the disease. For the clarification of blood picture diseases, various blood values and, if necessary, bone marrow parameters (including disease-specific genetic tests) are routinely determined.

Brief summary in scientific language

Classical BCR-ABL negative MPNs which include polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are a group of rare chronic stem cell disorders with an annual incidence rate ranging from 0.44 to 5.87/105 and a median age at diagnosis of 65 years. MPNs are characterized by clonal myeloproliferation, elevated pro-inflammatory cytokines secreted from malignant and non-malignant hematopoietic cells, and persistent hyper-activation of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) signalling pathway driven by mutations in JAK2, Calreticulin (CALR), and MPL genes in the majority of patients. Yet, causes behind the extreme heterogeneity in clinical and histopathological phenotypes of MPNs remain ill defined. In particular, MPNs in adolescents and young adults (AYA) from 16 and 39 years who constitute 2.2–6.6% of MPN cases seem to be genetically and phenotypically distinct entities. Recently, we identified recurrent somatic concomitant classical and/or noncanonical JAK2- and MPL-mutations in JAK2V617F- and MPLW515-positive myelofibrosis patients with genotype-phenotype associations with an age-dependency. Many of these mutations might act as “Significantly Mutated Genes” contributing to the pathogenesis and phenotypic heterogeneity. Second, it is not known to what extent a tumor-derived secretome conditions the bone marrow and spleen. Targeting the physiologic effects of altered inflammatory pathways and processes rather than their individual gene component might provide an opportunity to target “driver” rather than “bystander” inflammatory responses to improve patient outcomes. Thirdly, the impact of a “functionally relevant” genotype and inflammatory profile on debilitating and some-times life-threatening thrombotic events in patients with MPNs needs further elucidation. To identify the differences in genotypes between AYAs and Elderly using Whole exome sequencing (WES). Integration of WES data with RNA-sequencing will reveal gene expression signatures which is intended to be the basis for describing real driving cancer/inflammation-causing mutations in the background of stochastic passenger events without functional consequence. Clinical data annotation to WES and RNA-sequencing data could predict a role of specific gene networks and/or combinatorial mutational events in certain clinical and/or laboratory repertoires in AYAs and Elderly.