Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy

Abstract

• Early postnatal loss of Pten protein in mice with Nf1 haploinsufficiency causes a fatal juvenile myeloproliferative neoplasm.• Akt and MAPK activities are elevated in juvenile mice with Nf1 haploinsufficiency and Pten protein loss.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 mitogenactivated 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. (Blood. 2016;127(15):1912-1922

miR‑494‑3p regulates lipopolysaccharide‑induced inflammatory responses in RAW264.7 cells by targeting PTEN

“…TLR4, a member of the TLR family, interacts all four Toll-interleukin receptor domain-containing adaptor proteins to induce inflammatory responses; stimulation of TLR activates the NF-κB pathway (24). Based on a previous study, Akt1 activation is enhanced in PTEN-/-cells (25). This suggests that PTEN might augment TLR4-induced inflammatory responses by suppressing Akt1 activation (17).…”

Biomodulatory Treatment With Azacitidine, All-trans Retinoic Acid and Pioglitazone Induces Differentiation of Primary AML Blasts Into Neutrophil Like Cells Capable of ROS Production and Phagocytosis

“…Furthermore, reactivation of KLF4 expression through modulation of PPARγ signaling, exerted a multifaceted tumor-suppressive effect in CDX2 positive myeloid leukemia cell lines and primary AML blasts ( Faber et al, 2013 ), suggesting PPARγ agonists as a therapeutic modality in a large proportion of AML patients. As phosphatase and tensin homolog (PTEN) is one of the primary targets of PML/RARA in APL ( Noguera et al, 2016 ), and loss of PTEN protein plays a critical role in determining the disease severity in myeloid malignancies ( Liu et al, 2016 ), up-regulation of non-mutated PTEN by PGZ ( Patel et al, 2001 ) could be an additional molecular mechanism explaining the combined activity of ATRA/AZA/PGZ. In vivo , administration of PPARγ agonists additionally induced BM adipogenesis, which rescued healthy hematopoietic maturation while repressing leukemia growth ( Boyd et al, 2017 ).…”

The expression pattern of Bcl11a, Mdm2 and Pten genes in B‐cell acute lymphoblastic leukemia

“…The study of Liu et al. suggests that the timing of the loss of Pten protein plays a critical role in determining the disease severity in myeloid malignancies …”