Approximately 10% of patients with myeloproliferative neoplasms — such as polycythemia vera or essential thrombocythemia — have mutations in Janus kinase 2 (JAK2) and TET methylcytosine dioxygenase 2 (TET2). The authors sequenced TET2 in 246 patients carrying the JAK2V617F mutation and identified 24 patients who had both mutations. Subclone analyses were carried out to determine the order in which mutations were acquired; these experiments also established that most patients had clonal stability. Within the cohort, 12 patients had first acquired JAK2 mutations (JAK2-first), and 12 had initial TET2 mutations (TET2-first). TET2-first patients were significantly older at disease diagnosis than JAK2-first patients (this was also confirmed in a second cohort of 24 more patients). Furthermore, JAK2-first patients were more likely to have a diagnosis of polycythemia vera than essential thrombocythemia, and had a greater risk of thrombosis.
The two patient groups had different ratios of immature haematopoietic progenitors, so the authors analysed individual haematopoietic stem and progenitor cells (HSPCs) isolated from patients and cultured in vitro, and found that proliferation was increased in JAK2V617F single-mutant cells, but not in double-mutant cells from either TET2-first or JAK2-first patients, suggesting that the TET2 background affects the ability of JAK2V617F to promote proliferation. In addition, progenitor formation was decreased by JAK2 mutations in TET2-first patients, but increased by TET2 mutations in JAK2-first patients. Genotyping was consistent with this result, showing that the HSPC compartment contained primarily single-mutant cells in TET2-first patients and double-mutant cells in JAK2-first patients. Interestingly, JAK2-first patients had similar distributions of genotypes throughout the haematopoietic hierarchy, but the proportion of double-mutant cells in TET2-first patients increased in later stage erythroid and megakaryocytic progenitors. These data suggest that TET2 mutations increase the fitness of progenitors, and that JAK2 mutations promote differentiation into more committed progenitors.
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