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• W2969221208 endingPage "1744" @default.
• W2969221208 startingPage "1730" @default.
• W2969221208 abstract "Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression, we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to induce splenomegaly, thrombocytopenia, megakaryocytic dysplasia, and a propensity for chronic granulocytosis; phenotypes that closely resemble those observed in patients harboring del(20q). In a JAK2-V617F model, heterozygous Hippo kinase inactivation led to accelerated development of lethal myelofibrosis, recapitulating adverse MPN disease progression and revealing a novel genetic interaction between these 2 molecular events. Quantitative serum protein profiling showed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1β and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-κB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1β production in the JAK2-V617F MPN model. This study identified Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies and revealed a novel molecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition." @default.
• W2969221208 created "2019-08-29" @default.
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• W2969221208 date "2019-08-21" @default.
• W2969221208 modified "2023-10-06" @default.
• W2969221208 title "Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation" @default.
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• W2969221208 doi "https://doi.org/10.1182/blood.2019000170" @default.
• W2969221208 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6856986" @default.
• W2969221208 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31434702" @default.
• W2969221208 hasPublicationYear "2019" @default.
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