Myeloproliferative neoplasms (MPN), comprising polycythemia vera, essential thrombocythemia and myelofibrosis, are chronic hematological malignancies with variable progression rates. Whilst mutations in JAK2, CALR and MPL are known to drive the phenotype of these cancers, little is known about when these mutations are acquired during the lifetime of individual patietn's and the dynamics of the clonal expansion that subsequently occurs within the bone marrow. In the first part of my talk, I will discuss some recent work we have been doing to address questions around the origin of these cancers.
Over the last ten years, with large scale sequencing studies of MPN cohorts, the wider mutational landscape and degree of genomic heterogeneity amongst patients as become apparent. Somatic mutations within MPNs have been been demonstrated to hold prognostic value, both for patient survival and disease transformation. In the second part of my talk, I discuss recent published work where we sequenced the coding exons from 69 myeloid cancer genes in 2035 MPN patients, comprehensively annotating driver mutations and copy number changes. We developed a genomic classification for MPNs and multistage prognostic models for predicting individual patient outcomes. We defined 8 genomic subgroups exhibiting distinct clinical phenotypes, including diagnostic blood counts, risk of leukemic transformation and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in chronic phase MPN and myelofibrosis. This work demonstrated how comprehensive genomic sequencing can identify distinct genetic subgroups of diseand to provide an MPN classification that is based on causal biological mechanisms. Integration of genomic data with clinical parameters enables personalized predictions of patient outcome and can support clinical management of MPN patients.