Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells.

@article{Rao2009InhibitionON,
  title={Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells.},
  author={Sudhir Rao and J. O'neil and C. Liberator and J. Hardwick and Xudong Dai and Theresa Zhang and E. Tyminski and Jing Yuan and N. Kohl and V. Richon and L. V. D. van der Ploeg and P. Carroll and G. Draetta and A. Look and P. Strack and C. Winter},
  journal={Cancer research},
  year={2009},
  volume={69 7},
  pages={
          3060-8
        }
}
NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced… Expand
Inhibition of γ-secretase activity synergistically enhances tumour necrosis factor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5.
TLDR
Using immunofluorescence and western blotting, γ-secretase inhibition represents a potential therapeutic strategy to overcome TRAIL resistance for the treatment of T-ALL. Expand
Recent advances on NOTCH signaling in T-ALL.
TLDR
The current understanding of NOTCH1-induced transformation, the mechanisms of action of oncogenic NotCH1 in T-ALL and the therapeutic and prognostic implications of notCH1 mutations in T -ALL are reviewed. Expand
The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights theExpand
Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner
TLDR
The finding suggests that GSI has other functions besides inhibiting Notch signaling in T-ALL and incorporating GSI into the conventional regimen containing VCR may offer therapeutic advantage by potentiating VCR treatment in leukemia patients. Expand
MRK003, a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma
TLDR
The impact of MRK003, an inhibitor of this pathway, on myeloma and lymphoma cells is investigated and shows time-dependent decrease in levels of the notch intracellular domain, Hes1 and c-Myc. Expand
The role of NOTCH 1 signaling in TALL
The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformationExpand
Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia.
TLDR
Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-all cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells. Expand
The role of NOTCH1 signaling in T-ALL.
  • A. Ferrando
  • Biology, Medicine
  • Hematology. American Society of Hematology. Education Program
  • 2009
TLDR
New therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. Expand
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia
TLDR
A role for epigenetic heterogeneity in leukemia resistance is established that may be addressed by incorporating epigenetic modulators in combination therapy, and the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Expand
Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures
TLDR
The PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro, highlighting the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer. Expand
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References

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Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
TLDR
Findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL. Expand
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors
TLDR
It is shown that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI and most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRk-003, implying that residual NOTCH signaling in T-ALLs with FBw7 mutations contributes to GSI resistance. Expand
Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia.
TLDR
T-ALL cell growth was suppressed in a highly synergistic manner by simultaneous treatment with the mTOR inhibitor rapamycin and GSI, which represents a rational drug combination for treating this aggressive human malignancy. Expand
Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines.
TLDR
The data suggest that the aberrantly high Notch signaling in T-ALL maintains SKP2 at a high level and reduces p27Kip1, leading to more rapid cell cycle progression. Expand
Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling.
TLDR
Together, these data strengthen the rationale for using gamma-secretase inhibitors therapeutically and suggest that programmed cell death may contribute to reduction of tumor burden in the clinic. Expand
c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.
Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from anExpand
Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia
TLDR
It is reported here that constitutively active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-β in bone marrow hematopoietic stem cells and progenitors. Expand
The Notch1/c-Myc Pathway in T Cell Leukemia
TLDR
These studies begin to delineate how notch1 mediates cellular transformation and raises the possibility that the Notch1/c-Myc pathway may contribute to human breast cancer and potentially other solid tumors. Expand
Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation
TLDR
This novel pathway involving Notch/SKP2/CKIs connects a cell surface receptor with proximate mediators of cell cycle activity, and suggests a mechanism by which a known physiologic mediator of cell fate determination interfaces with cell cycle control. Expand
Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc
TLDR
The Notch1 molecular signature in mouse T-ALL is defined and mechanistic insight is provided as to how notch1 contributes to human T-all as well as identifying c-myc as a novel, direct, and critical NotCh1 target gene in T-cell leukemia. Expand
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