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Find video protocols related to scientific articles indexed in Pubmed.
Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms.
Blood
PUBLISHED: 10-05-2014
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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.
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Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-? in a murine model of polycythemia vera.
Blood
PUBLISHED: 03-13-2013
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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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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.