Signaling mutations (e.g. JAK2V617F) and mutations in genes involved in epigenetic regulation (e.g. TET2) are the most common co-occurring classes of mutations in myeloproliferative neoplasms (MPN). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPN such as myelofibrosis and leukemic transformation, suggesting that they may co-operate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSC). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and non-overlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSC and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This works provides insights into the functional consequences of JAK2V617F-TET2 co-mutation in MPN, particularly as it pertains to HSC.
Interferon-? (IFN?) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFN? reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFN? on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFN? on Jak2V617F MPN-propagating stem cells in vivo. We report that IFN? treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFN? treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFN? on Jak2V617F mutant and normal hematopoiesis and suggest that IFN? achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFN? and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy.
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