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Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy
UMass Chan Affiliations
Department of Medicine, Division of Hematology/OncologyDocument Type
Journal ArticlePublication Date
2016-04-14
Metadata
Show full item recordAbstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN). JMML leukemogenesis is linked to a hyperactivated RAS pathway, with driver mutations in the KRAS, NRAS, NF1, PTPN11, or CBL genes. Previous murine models demonstrated how those genes contributed to the selective hypersensitivity of JMML cells to granulocyte macrophage-colony-stimulating factor (GM-CSF), a unifying characteristic in the disease. However, it is unclear what causes the early death in children with JMML, because transformation to acute leukemia is rare. Here, we demonstrate that loss of Pten (phosphatase and tensin homolog) protein at postnatal day 8 in mice harboring Nf1 haploinsufficiency results in an aggressive MPN with death at a murine prepubertal age of 20 to 35 days (equivalent to an early juvenile age in JMML patients). The death in the mice was due to organ infiltration with monocytes/macrophages. There were elevated activities of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) in cells at physiological concentrations of GM-CSF. These were more pronounced in mice with Nf1 haploinsufficiency than in littermates with wild-type Nf1,but this model is insufficient to cause cells to be GM-CSF hypersensitive. This new model represents a murine MPN model with features of a pediatric unclassifiable mixed MDS/MPN and mimics many clinical manifestations of JMML in terms of age of onset, aggressiveness, and organ infiltration with monocytes/macrophages. Our data suggest that the timing of the loss of PTEN protein plays a critical role in determining the disease severity in myeloid malignancies. This model may be useful for studying the pathogenesis of pediatric diseases with alterations in the Ras pathway.Source
Blood. 2016 Apr 14;127(15):1912-22. doi: 10.1182/blood-2015-05-646216. Epub 2016 Jan 13. Link to article on publisher's siteDOI
10.1182/blood-2015-05-646216Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40058PubMed ID
26764354Notes
Full author list omitted for brevity. For full list of authors see article.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1182/blood-2015-05-646216