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http://purl.uniprot.org/citations/35609769http://www.w3.org/2000/01/rdf-schema#comment"

Background

Myeloproliferative neoplasms (MPN) are a group of chronic haematological disorders. At the molecular level of MPN cells, the gain-of-function mutation V617F of the Janus kinase 2 (JAK2) leads to a constitutive activation of the downstream signaling cascade and is a conventional criteria for diagnosis. Here, the functional role of the tumor suppressor SHIP1 (SH2 domain containing inositol-5 phosphatase 1) in the pathogenesis of MPNs was investigated.

Methods

Primary blood samples of MPN-patients were analysed using Western Blot technique regarding the level of SHIP1 expression. Moreover, SHIP1 and SHIP1-mutations were lentivirally transduced in the JAK2-V617F-positive UKE-1 cell line and expression was monitored over time. In addition, we examined SHIP1 reconstitution by inhibition of JAK2-V617F. Furthermore, we transfected SHIP1-expressing cells with a JAK2-V617F respectively a BCR-ABL construct and investigated changes in SHIP1 expression.

Results

Four out of five MPN-patient samples showed a loss or a reduction in SHIP1 expression. We identified JAK2 as a negative regulator of SHIP1 expression in MPN cells and inhibition of JAK2-V617F implicates a reconstituted SHIP1 expression. This is significant because SHIP1 negatively regulates the AKT signaling pathway and in consequence the reconstitution of SHIP1 expression leads to a decreased cell growth. Moreover, we examined the impact of SHIP1 and patient-derived SHIP1-mutations on AKT phosphorylation and show the benefit of a combined therapy in MPN cells with inhibitors of the AKT/mTOR pathway.

Conclusion

In summary, the data suggest that SHIP1 may play a role during the development of MPNs and could be the basis for establishing a targeted therapy."xsd:string
http://purl.uniprot.org/citations/35609769http://purl.org/dc/terms/identifier"doi:10.1016/j.biocel.2022.106229"xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/author"Jucker M."xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/author"Ehm P."xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/author"Dally L."xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/author"Gluck M."xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/date"2022"xsd:gYear
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/name"Int J Biochem Cell Biol"xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/pages"106229"xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/title"JAK2-V617F is a negative regulation factor of SHIP1 protein and thus influences the AKT signaling pathway in patients with Myeloproliferative neoplasm (MPN)."xsd:string
http://purl.uniprot.org/citations/35609769http://purl.uniprot.org/core/volume"149"xsd:string
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