Genetic lesions and clinical implications in myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are a group of chronic hematologic diseases, which are characterized by an over production of mature blood cells. The term MPN summarizes four main hematologic diseases: Chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). In this group of malignancies, CML patients can be identified by a chromosomal translocation, the Philadelphia chromosome. Patients with ET, PV and PMF share genetic markers, and can only be distinguished by clinical parameters. Currently, it is still unclear, how a specific genetic alteration can lead to different clinical phenotypes.
In the present thesis, we utilized novel NGS technologies and analyzed more than 100 genes in parallel to find secondary somatic mutations with impact on the phenotype of Ph-negative MPN patients. We also analyzed the temporal order of acquisition of these mutations and compared our results between adult MPN patients and rare pediatric cases. Our results show that in adult patients, the number of somatic mutations correlates with adverse survival and transformation to AML. Further, we report cases of patients who carry clones of TP53 mutations for multiple years and only when these clones expand, the MPN phenotypes of these patients progresses to AML. In pediatric MPN cases, we found a different mutational landscape and less genetic mutations per patient.
In the second part of the thesis, we analyzed patients with a very low mutant JAK2 allele burden and found that the MPN clone in these patients expands in the platelet and red cell lineages. Furthermore, we analyzed the genetic alterations of a large combined cohort to uncover instructive effects on the MPN phenotype of less frequently mutated genes. Finally, we show how different genetic alterations may modulate the MPN phenotype and propose a model of disease evolution and risk stratification in correlation to mutational events.