Ph-chromosome-negative myeloproliferative neoplasms: clonal dynamics are the name of the game

Ph-chromosome-negative myelo-proliferative neoplasms (MPNs) are characterized by over-production of mature blood cells driven by acquired somatic variants in JAK2, CALR and MPL in most instances. Ph-chromosome-negative MPNs are genetically and clinically heterogeneous. These variants are detected in blood cells of > 3 per cent of normal people but few develop Ph-chromosome-negative MPNs. People with Ph-chromosome-negative MPNs often have sub-clones which are important for disease evolution. Clonal architecture is shaped by hereditary factors, inflammation and environmental exposures such as some chemicals and cytotoxic drugs. Clonal architecture correlates with phenotype, prognosis and risk of leukaemia transformation. Recent advances like single-cell DNA sequencing (scDNA-seq) provide data on the clonal dynamics of Ph-chromosome-negative MPNs. We comprehensively review genomic profiles, clonal evolution and risk of leukaemia transformation, emphasizing the importance of clonal architecture.