Myeloproliferative neoplasms (MPN) are a group of hematological malignancies primarily driven by somatic mutations and chromosomal aberrations. In the recent years significant amount of evidence has been accumulating on the importance of hereditary factors in MPN. Familial clustering, cases of biclonal MPN and phenotypic diversity in the presence of the same mutation have provided a solid basis for research in MPN germline genetics. Despite comprehensive clinical characterization of familial MPN, the major germline mutations responsible for MPN susceptibility have not been found. The same is true for the association of MPN with common SNPs in the population. We performed a detailed study of germline genetic factors influencing MPN from multiple aspects. In order to study familial MPN, we first developed a nonparametric linkage analysis algorithm for high-throughput genotyping data. We validated the method on three families with known germline causative mutations and then applied it to a family with five affected MPN cases. Combining linkage analysis with exome sequencing and downstream validation of the identified hits, we found a mutation in RBBP6 gene as the candidate susceptibility gene. Additional screening in other families with MPN yielded another two families with germline RBBP6 mutations. RBBP6 is interacting with p53 and presumably the effect of mutation is mediated through p53 pathway. Moreover, we have shown an important role of p53 pathway in MPN, particularly in leukemic transformation, coming from the somatic genetics side. We have also contributed to the understanding of the role of common germline predisposition to MPN. We have identified the strongest common predisposition for JAK2-positive MPN: the 'GGCC' haplotype spanning JAK2 locus. Additionally, we have shown that although JAK2 'GGCC' haplotype confers the same risk in familial MPN, it cannot explain familial clustering of MPN. Finally, we have identified a phenomenon of the interaction of somatic genetic aberrations and germline mutations. We have shown that a deleterious heterozygous mutation can influence disease phenotype when combined with acquired chromosomal aberration.
Overall, it seems that the inherited factors have quite an important role in MPN. The interconnection and overlap of somatic and germline genetics is particularly intriguing and will provide a new dimension in MPN research.