| identifier |
PRJDB3992 |
| type |
bioproject |
| sameAs |
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| organism |
Mus musculus
|
| title |
Ezh2 loss cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition |
| description |
EZH2 is a component of polycomb repressive complex (PRC) 2 and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with worse outcome in patients with myeloproliferative neoplasms (MPN), particularly with primary myelofibrosis (PMF). To understand how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for Ezh2 conditional deletion and a JAK2V617F transgene. Deletion of Ezh2 in JAK2V617F mice markedly promoted the development of MF, indicating a tumor suppressor function of EZH2 in PMF. Ezh2 loss in JAK2V617F hematopoietic stem and progenitor cells caused significant reduction in H3K27 trimethylation (H3K27me3) levels, followed by induction of H3K27 acetylation (H3K27ac) preferentially at promoter regions of PRC2 targets. These epigenetic switches were closely associated with activation of PRC2 targets including Hmga2, an oncogene implicated in the pathogenesis of PMF. Importantly, treatment of JAK2V617F/Ezh2 null mice with a bromodomain inhibitor significantly attenuated the levels of H3K27ac as well as expression of Ezh2/PRC2 targets, resulting in abrogation of MF-initiating cells. Collectively, EZH2 insufficiency not only cooperates with active JAK2 to induce MF but also confers sensitivity to bromodomain inhibitors on MF-initiating cells. Our findings provide a novel epigenetic-based rationale for the treatment of PMF. |
| data type |
Epigenomics
|
| publication |
|
| properties ▽ |
{...}
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| dbXrefs |
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| distribution |
JSONJSON-LD
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| Download |
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| status |
public |
| visibility |
unrestricted-access |
| dateCreated |
2015-06-11T07:09:29+09:00 |
| dateModified |
2016-05-23T13:03:38+09:00 |
| datePublished |
2016-05-23T13:03:37+09:00 |