title: Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Winthrop P. Rockefeller Cancer Institute.
authors.forename: Y Lucy
authors.identifier: http://orcid.org/0000-0001-8587-8338
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Winthrop P. Rockefeller Cancer Institute.
authors.forename: Yan
authors.identifier: http://orcid.org/0000-0001-8180-3670
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Winthrop P. Rockefeller Cancer Institute.
authors.forename: Cody
authors.initials: C
authors.lastname: Webster
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Biostatistics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Shelly Y
authors.initials: SY
authors.lastname: Lensing
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL;
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ni
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Division of Pediatric Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors.forename: Natalia
authors.initials: N
authors.lastname: Colorado
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Winthrop P. Rockefeller Cancer Institute.
authors.forename: Zhifu
authors.identifier: http://orcid.org/0000-0003-0602-9827
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0003-1776-4325
authors.initials: M
authors.lastname: Hauer-Jensen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Shaoguang
authors.identifier: http://orcid.org/0000-0002-6141-6312
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Daohong
authors.identifier: http://orcid.org/0000-0002-7771-6299
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Winthrop P. Rockefeller Cancer Institute.
authors.forename: Peter D
authors.identifier: http://orcid.org/0000-0002-9764-2434
authors.initials: PD
authors.lastname: Emanuel
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D018631:ras Proteins / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D018631:ras Proteins