Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA306357 | ENA |
REPOSITORIES: ENA
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Project description:Apoptosis Repressor with Caspase Recruitment Domain (ARC) was recently found to be highly expressed in solid tumors and in blast cells of patients with acute myeloid leukemia (AML). In this study, we assessed the functional and molecular consequences of loss of ARC on the hematopoietic system. We found, unexpectedly, that deletion of Nol3 (the gene that encodes ARC) in mice leads to development of a myeloproliferative neoplasm (MPN) resembling primary myelofibrosis (PMF). Nol3-/--induced MPN is transplantable into secondary recipient mice and is characterized by anemia, thrombocytopenia, extramedullary hematopoiesis, and bone marrow fibrosis. Despite an overall reduction in bone marrow cellularity Nol3-/- MPN mice have an expanded Thy1+LSK stem cell population with increased cell cycling, in addition to a myelomonocytic differentiation bias. Molecularly, the Nol3-/--induced phenotype is, at least in part, mediated by activation of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) and MYC. Nol3-/- MPN Thy1+LSK cells show significant molecular similarities with primary CD34+ cells isolated from patients with PMF. Furthermore, we found that Nol3 is deleted in patients with human myeloid malignancies and has decreased expression in a subset of patients with de novo AML. Our results reveal a novel role of Nol3 in normal hematopoiesis and in the pathogenesis of myeloid malignancies. To obtain insight into the molecular mechanism of the Nol3-/- -induced MPN, we performed gene expression profiling on Thy1+LSK bone marrow cells from Nol3+/+ and Nol3-/- MPN mice
2017-02-17 | GSE76121 | GEO
Project description:Myeloproliferative Neoplasms (MPNs) are a heterogenous group of hematologic cancers characterized by excessive JAK/STAT signaling. Mutations of JAK2 signaling components are among the most common drivers of MPN, but alterations in Suppressors of Cytokine Signaling (SOCS) proteins have been implicated in MPN pathogenesis and progression. Cullin 5 (Cul5) is an E3 ubiquitin ligase known to work with suppressors of cytokine signaling (SOCS) proteins which regulate the JAK/STAT pathway. Here we report that mice lacking Cul5 in hematopoietic stem and progenitor cells (HSPCs) develop an MPN-like disease with characteristic features including splenomegaly, extramedullary hematopoiesis, thrombocytosis, and anemia. Cul5-deficient HSPCs have higher phospho-STAT5 (pSTAT5) levels following stimulation with IL-3 and outcompete WT HSPCs in bone marrow transplants. Immunoprecipitation of Cul5 in cultured HSPCs showed interactions with STAT5 as well as several well-studied substrate receptors including SOCS2, SOCS6, ASB2, ASB3, ASB6 and CIS, as well as lesser-known WSB1 and LRRC41. Proteome analysis of Lin- Sca-1+ c-kit+ (LSK) cells from Cul5Vav-Cre bone marrow shared many upregulated genes and signatures with MPN patient cells. Finally, treatment with ruxolitinib, a JAK1/2 inhibitor, ameliorated MPN symptoms in Cul5-deficient mice. These studies demonstrate a novel function of Cul5 in hematopoiesis, delineating a contributing role in MPN.
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