FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors

@article{Oneil2007FBW7MI,
  title={FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to $\gamma$-secretase inhibitors},
  author={J. O'neil and J. Grim and P. Strack and Sudhir Rao and D. Tibbitts and C. Winter and J. Hardwick and M. Welcker and J. Meijerink and R. Pieters and G. Draetta and R. Sears and B. Clurman and A. Look},
  journal={The Journal of Experimental Medicine},
  year={2007},
  volume={204},
  pages={1813 - 1824}
}
γ-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL… Expand
Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells.
TLDR
Investigation of the mechanisms of GSI sensitivity across a panel of T-ALL cell lines yielded an approach for patient stratification based on pathway activity and a rational combination strategy for enhanced response to GSI, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of G SI action. Expand
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TLDR
This study focused on γ‐secretase inhibitors as a potential therapeutic target for the design of anti‐NOTCH1 therapies for the treatment of T‐cell acute lymphoblastic leukemias and lymphomas. Expand
The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability
TLDR
It is demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy. Expand
High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia.
TLDR
Findings in primary tumors extend recent work using human T-all cell lines and xenografts and suggest that the Notch/Myc signaling axis is of predominant importance in understanding both the selective pressure for Notch mutations in T-ALL and response and resistance of T- ALL to Notch pathway inhibitors. Expand
Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias.
TLDR
It is shown that activated NOTCH1 and ZMIZ1 collaborate to induce T-ALL in mice, and the importance of identifying genetic collaborations between parallel leukemic pathways that may be therapeutically targeted is shown. Expand
FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL.
TLDR
FBXW7 mutations coincided with an increase in NotCH1 target gene expression and explain a proportion of patients characterized by dysregulated NOTCH1 signaling, and activated NICD levels were increased and remained stable upon translation inhibition. Expand
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TLDR
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Mechanisms of NOTCH1 Mediated Leukemogenesis: A Dissertation
TLDR
Evidence is provided that Notch1 can be successfully targeted in vivo and that notch inhibition, with γ-secretase inhibitors (GSIs), significantly extends the survival of leukemic mice and extends survival in a mouse xenograft model. 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
Collaborating Pathways that Functionally Amplify NOTCH1 Signals in T-Cell Acute Lymphoblastic Leukemia.
TLDR
Collaborating oncogenic networks are essential to functionally enhance NOTCH1 signaling to leukemogenic levels, and cancers resist GSI by activating collaborating pathways to bypass the effects of Notch1 inhibition. Expand
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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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It is suggested that interactions between c- myc and Fbw7gamma within the nucleolus regulate c-Myc's growth-promoting function and that c-myc activation is likely to be an important oncogenic consequence of FbW7 loss in cancers. Expand
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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
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TLDR
Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence and Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. Expand
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TLDR
Analysis revealed Notch1 activating mutations in 12 of 17 Plstc/+ lymphomas (70%), analogous to those in human T-ALL. Expand
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TLDR
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TLDR
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