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

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Abstract Text:

Jennifer O'Neil,Jonathan Grim,Peter Strack,Sudhir Rao,Deanne Tibbitts,Christopher Winter,James Hardwick,Markus Welcker,Jules P Meijerink,Rob Pieters,Giulio Draetta,Rosalie Sears,Bruce E Clurman,A Thomas Look,

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.

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Publishing Authors By Initials

J O'Neil,J Grim,P Strack,S Rao,D Tibbitts,C Winter,J Hardwick,M Welcker,JP Meijerink,R Pieters,G Draetta,R Sears,BE Clurman,AT Look,

For similar enzymes and coenzymes: enzymes: ligases: ubiquitin-protein ligase complexes: ubiquitin-protein ligases research abstracts see: enzymes and coenzymes: enzymes: ligases: ubiquitin-protein ligase complexes: ubiquitin-protein ligases research

PUBMED ID PMID:

MEDLINE DATE:

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of experimental medicine

VOLUME: 204

Page Numbers: 1813-24

Journal Abbreviation: J. Exp. Med.

ISSN: 0022-1007

DAY: 23

MONTH: 07

YEAR: 2007

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985109

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Keywords Mesh Terms:

KEYWORDS: Ubiquitin-Protein Ligases

MESH TERMS: genetics

Chemical & Substance for Abstract: FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Information

Substance Name: Ubiquitin-Protein Ligases

Registry Number: EC 6.3.2.19

Grant and Affiliation Information for FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.

AFFILIATION: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01CA84069

ACRONYM: CA

MEDLINETA: J Exp Med

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors Related Publications

• A creative response meets community need/enriches hospital.
• Activating mutations in ALK provide a therapeutic target in neuroblastoma.
• Acute lymphoblastic leukaemia.
• Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3.
• Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation.
• Combined source-detector response characteristics.
• Dominant-interfering C/EBPalpha stimulates primitive erythropoiesis in zebrafish.
• FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.
• Identification of structural aberrations in cancer by SNP array analysis.
• Inhibition of Jak1-dependent signal transduction in airway epithelial cells infected with adenovirus.
• Mechanisms of transcription factor deregulation in lymphoid cell transformation.
• Myelopoiesis in the zebrafish, Danio rerio.
• NOTCH and PI3K-AKT pathways intertwined.
• Type 2 diabetes in native Hawaiians and Pacific Islanders in Hawaii.