What are the molecular mechanisms driving the switch from MPNs to leukemia?

Myeloproliferative neoplasm-blast phase (MPN-BP) is a form of acute leukemia which is distinct from de novo acute myeloid leukemia with each entity being characterized by specific complex cytogenetic abnormalities and myeloid gene mutational patterns. MPN-BP patients have a particularly dismal prognosis with a medium overall survival of 5.8 months with currently available therapies. Large-scale sequencing studies have unraveled the mutational landscape of the chronic MPNs and MPN-BP, demonstrating importance of clonal heterogeneity and the role of somatic mutations in disease progression and their use to determine patient outcomes. JAK inhibitors represent the standard of care for intermediate/high-risk MF patients and have been shown to improve clinical symptoms. However, this therapeutic approach leads to a modest reduction in the variant allele frequency of the known MPN driver mutations in most patients and does not substantially delay or prevent the evolution to MPN-BP. In this article, we will review molecular mechanisms driving the progression from chronic MPNs to a BP, the impact of genetic changes on MPN-BP evolution, and the role of clonal evolution in response to JAK inhibitor therapy and disease progression. We will also discuss our ongoing functional studies of cells responsible for the development of MPN-BP.