The roles of sex and genetics in the MPN.

The Philadelphia chromosome negative myeloproliferative neoplasms(MPNs), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are acquired hematopoietic stem cell disorders driven by activating mutations of intracellular signal transduction pathways that control the production of circulating blood cells. The MPN are characterized clinically by marked variation in degrees of vascular risk, familial clustering, and evolution to myelofibrosis and acute leukemia. MPN disease presentations and outcomes are highly variable, and are markedly influenced by both sex and germline genetic variation. This chapter will focus on the evidence of sex and germline genetic background as modifiers of MPN development and outcomes. Large population genome wide association studies in both clonal hematopoiesis and MPN have revealed novel mechanisms, including inflammatory pathways and genomic instability, which further our understanding of how sex and genetic background mediate MPN risk. Recent advances in our understanding of clonal hematopoiesis and MPN development in various contexts informs the mechanisms by which sex, inflammation, exposures and genetics influence MPN incidence and outcomes, and provide opportunities to develop new strategies for prognostics and therapeutics in the MPN.