JAK2 and TET2 mutations temporally linked with myeloproliferative disorder outcomes

1. The temporal relationship between acquisition of JAK2 and TET2 mutations influenced clinical outcome in affected patients with myeloproliferative disorders.

2. As JAK2-first colonies proved more responsive to targeted JAK1 and JAK2 inhibition, genetic mutation sequencing mapping may present healthcare professionals with novel strategy to target therapy for cancer patients.

Evidence Rating Level: 2 (Good)

Study Rundown:  In this study, researchers discuss the consequences of JAK2 and TET2 mutations in a patient-derived cell population enriched with myeloprolferative disorders with JAK2 V617F mutations (polycythemia vera, essential thrombocythemia, and myelofibrosis). It was found that the order in which either of the two aforementioned mutations occurred dictated the resulting cell type that was favored to proliferate. When the TET2 mutation was acquired initially hematopoietic stem and progenitor cells were favored; however, when the JAK2 mutation was acquired first, megakaryocyte and erythrocyte cells were favored. The sequence in which the genes presented resulted in respective diseases; for instance JAK2-first patients, compared to TET2-first patients, had a greater likelihood of presenting with polycythemia vera and increased risk of thrombosis.

In conclusion, a comprehensive understanding and application of such mutations and their sequential presentation could better aid physicians in providing targeted therapy. While deciphering the potential algorithms with such mutations would be laborious, it may open a novel strategy with which healthcare professionals diagnose and therapeutically approach cancer treatments in the future.

Click to read the study, published today in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: Clonal evolution in cancer

In-Depth [retrospective cohort]: This study highlights the importance of not only focusing on the mutation that gives rise to a certain disease, but also to the sequential presentation of such mutations, as clinical outcomes were affected depending on the temporal sequence of genetic abnormalities. 246 patients who carried both JAK2 and TET2 mutations had their exons sequenced. It was found that JAK2-first patients had a striking increase in the proportion of JAK2 V617F-homozygous colonies of erythroid burst-forming units compared to TET2-first patients (P<0.001). In contrast, in the TET2-first patients, there was a significant predominance of common myeloid progenitors over any other potential progenitors within the CD34⁺CD38⁺ section (P=0.001, when compared to JAK2­-­first patients). Compared to TET2­-first patients, JAK2-first patients presented at a significantly younger age (P=0.002), were more likely to present with polycythemia vera (P=0.05), and were more likely to have a thrombotic event (P=0.002 by multivariate analysis). There were also important findings for the relevance of mutation order for potential response to therapy: JAK2­-first colonies proved more responsive to ruxolitinib, an inhibitor of JAK1 and JAK2, than TET2-first colonies.

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