Relevant mouse model for human monocytic leukemia through Cre/lox-controlled myeloid-specific deletion of PTEN

Yu, Hongbo; Li, Yili; Gao, Chuanyun; Fabien, L.; Jia, Yong; Lu, Junjie; Silberstein, Leslie E.; Pinkus, Geraldine S.; Ye, Kun; Chai, Li; Luo, Hongbo

doi:10.1038/leu.2010.34

Cited by 22 publications

(32 citation statements)

References 8 publications

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“…No lymphadenopathy or thymus enlargement was found, differing substantially from previous models in which Pten deletion occurred at either the prenatal or the adult stage and in which the mice always died of AML or ALL in adulthood (Table 1; supplemental Table 4). [29][30][31]33 We also noticed that littermates with hemizygous Pten deletion or WT Pten did not show any overt disease symptoms during the 120-day observation, regardless of Nf1 background ( Figure 1A). Because our focus was primarily on juvenile leukemia, we studied the mice with only PtenD/D; Nf1 ; Nf1 1/2 and with WT (P , .001).…”

Section: Methodsmentioning

confidence: 75%

“…This reasoning may explain why Nf1-deficient mice with Pten loss developed a more severe MPN at a juvenile age, whereas other mice with PtenD/D induced in the prenatal or adulthood stages developed a latent and transient MPN but eventually transformed into acute leukemia in adulthood. 31,33 It is possible that the cells were able to accumulate more molecular defects during expansion, given a less aggressive course. Furthermore, it was reported that in vitro, somatic loss of Pten expression in cells with K-Ras D12/G64 is strongly correlated with resistance to MEK inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…22 Other groups reported that myeloid-specific somatic deletions of Pten in fetal or adult mice produced a transient MPN, with eventual death in adulthood from acute myeloid leukemia (AML) or ALL. [29][30][31] It was also reported that fetal and adult mouse HSCs display marked differences in their selfrenewal, differentiated cell output, and gene expression properties, with persistence of a fetal phenotype until 3 weeks after birth. 32 The role of Pten in regulating mouse hematopoiesis has been reported to be age dependent.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Yan

Webster

et al. 2016

Blood

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• 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

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Section: Methodsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Liu

Yan

Webster

et al. 2016

Blood

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“…The SALL4 transcription factor is involved in the maintenance of pluripotency and self-renewal of embryonic stem cells. [44][45][46] There are numerous transcription factors that bind the PTEN promoter region to regulate transcription. Various transcription factors can have positive (for example, Egr-1, Atf2, p53, CBP/p300, PPARg, CBF-1) or negative effects (for example, nuclear factor kappa from B cells, Snail1, Bmi-1, c-Jun, p53, PPARg, CBF-1) on PTEN transcription.…”

Section: Pseudo-pten and Other Oncogenes Decoys For Mirnasmentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…Further, the phenotypic similarities between AKT activation and Pten loss in progenitors suggests that the additive effects of activating both AKT and TORC1 signaling in Ptendeficient hemocytes might contribute to the more dramatic effects on terminal differentiation and premature release of LG hemocytes into circulation. Previous studies in vertebrates have shown that Pten loss (Yilmaz et al, 2006;Zhang et al, 2006) and AKT activation (Kharas et al, 2010) in HSCs as well as in myeloid progenitors (Yu et al, 2010) induces myeloproliferative disorder (MPD) and leukemia. Although reduced expression of TSC has been reported in a subset of acute leukemia patients (Xu et al, 2009), Tsc1 loss in HSCs is not sufficient to induce leukemia in mice (Chen et al, 2008).…”

Section: Differential Effects Ofmentioning

confidence: 99%

Multifaceted roles of PTEN and TSC orchestrate growth and differentiation of Drosophila blood progenitors

Dragojlovic-Munther

Martinez‐Agosto

2012

Development

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SUMMARYThe innate plasticity of hematopoietic progenitors is tightly regulated to supply blood cells during normal hematopoiesis and in response to stress or infection. We demonstrate that in the Drosophila lymph gland (LG) the tumor suppressors TSC and PTEN control blood progenitor proliferation through a common TOR-and 4EBP-dependent pathway. Tsc2 or Pten deficiency in progenitors increases TOR signaling and causes LG overgrowth by increasing the number of actively dividing cells that accumulate high levels of phosphorylated (p) 4EBP during a critical window of growth. These phenotypes are associated with increased reactive oxygen species (ROS) levels in the LG, and scavenging ROS in progenitors is sufficient to rescue overgrowth. Blood progenitor number is also sensitive to starvation and hypoxia in a TOR-dependent manner. Differences between Tsc1/2 and Pten function become apparent at later stages. Loss of Tsc1/2 autonomously increases p4EBP and decreases pAKT levels, expands the number of intermediate progenitors and limits terminal differentiation, except for a late induction of lamellocytes. By contrast, absence of PTEN increases p4EBP and pAKT levels and induces myeloproliferative expansion of plasmatocytes and crystal cells. This increased malignancy is associated with non-autonomous increases in p4EBP levels within peripheral differentiating hemocytes, culminating in their premature release into circulation and demonstrating potential non-autonomous effects of Pten dysfunction on malignancy. This study highlights mechanistic differences between TSC and PTEN on TOR function and demonstrates the multifaceted roles of a nutrient-sensing pathway in orchestrating proliferation and differentiation of myeloid-specific blood progenitors through regulation of ROS levels and the resulting myeloproliferative disorder when dysregulated.

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Relevant mouse model for human monocytic leukemia through Cre/lox-controlled myeloid-specific deletion of PTEN

Cited by 22 publications

References 8 publications

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

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

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Multifaceted roles of PTEN and TSC orchestrate growth and differentiation of Drosophila blood progenitors

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