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Order Matters

Cancers often accumulate mutations in a stepwise fashion, and researchers from the Cambridge Institute for Medical Research and elsewhere report in the New England Journal of Medicine that the order in which mutations crop up in patients with myeloproliferative neoplasms affects how their disease progresses.

Anthony Green and his colleagues screened 246 patients with a JAK2 V617F mutation for additional mutations in TET2, finding two dozen patients with both mutations. Blood samples obtained from the patients were grown as hematopoietic colonies to determine the mutation order — half the patients developed the JAK2 mutation first and half the TET2 mutation first, as GenomeWeb reports.

Patients who developed JAK2 mutations first were more likely to have polycythemia vera and present earlier with disease as they generated more megakaryocytic and erythroid cells. Meanwhile, New Scientist notes those patients who developed TET2 mutations first were more likely to develop full-blown leukemia but were less likely to develop blood clots.

"It's the first time we've been able to show that the order impacts both the clinical and biological features of the disease," first author David Kent tells the New Scientist.

The researchers note that TET2 mutations appeared to alter the transcriptional program that JAK2 V617F can activates, suggesting a possible molecular basis for these differences.

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