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Published on: February 21, 2018
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors
Jennifer O'Neil1, Jonathan Grim, Peter Strack
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Abstract:
gamma-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 samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. 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.
Insights
Mutations in the FBW7 gene cause resistance to gamma-secretase inhibitors (GSIs) in T cell acute lymphoblastic leukemia (T-ALL) by stabilizing NOTCH signaling and MYC. This resistance impacts targeted therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Gamma-secretase inhibitors (GSIs) target NOTCH signaling, a pathway often dysregulated in T cell acute lymphoblastic leukemia (T-ALL).
- Understanding GSI resistance mechanisms is crucial for developing effective T-ALL therapies.
Purpose of the Study:
- Investigate the basis for GSI resistance in T-ALL cell lines with constitutive NOTCH intracellular domain (NICD) expression.
- Identify genetic alterations contributing to resistance against NOTCH-targeted therapies.
Main Methods:
- Analyzed T-ALL cell lines and primary samples for mutations or deletions in the FBW7 gene.
- Assessed the binding of FBW7 mutants to NICD and MYC.
- Determined the effect of FBW7 mutations on NICD turnover and MYC degradation.
- Evaluated GSI (MRK-003) sensitivity in cell lines with FBW7 mutations.
- Measured NOTCH target gene expression (MYC, DELTEX1) following GSI treatment.
Main Results:
- FBW7 mutations or deletions were found in 7 of 7 examined T-ALL cell lines and 8.6% of primary T-ALL samples.
- FBW7 mutants failed to bind NICD, preventing its degradation and leading to NICD stabilization.
- Mutant FBW7 could not degrade MYC, suggesting co-stabilization of NICD and MYC.
- All T-ALL cell lines with FBW7 mutations exhibited resistance to the GSI MRK-003.
- Resistant cell lines showed incomplete down-regulation of NOTCH target genes MYC and DELTEX1 upon GSI treatment.
Conclusions:
- FBW7 mutations are a key mechanism of GSI resistance in T-ALL.
- Stabilization of NICD and MYC due to FBW7 loss-of-function contributes to leukemic transformation and GSI resistance.
- Targeting FBW7 or downstream pathways may overcome GSI resistance in T-ALL.
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