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NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols.

Abstract
Aberrant activation of the NOTCH1 pathway by inactivating and activating mutations in NOTCH1 or FBXW7 is a frequent phenomenon in T-cell acute lymphoblastic leukemia (T-ALL). We retrospectively investigated the relevance of NOTCH1/FBXW7 mutations for pediatric T-ALL patients enrolled on Dutch Childhood Oncology Group (DCOG) ALL7/8 or ALL9 or the German Co-Operative Study Group for Childhood Acute Lymphoblastic Leukemia study (COALL-97) protocols. NOTCH1-activating mutations were identified in 63% of patients. NOTCH1 mutations affected the heterodimerization, the juxtamembrane and/or the PEST domains, but not the RBP-J-κ-associated module, the ankyrin repeats or the transactivation domain. Reverse-phase protein microarray data confirmed that NOTCH1 and FBXW7 mutations resulted in increased intracellular NOTCH1 levels in primary T-ALL biopsies. Based on microarray expression analysis, NOTCH1/FBXW7 mutations were associated with activation of NOTCH1 direct target genes including HES1, DTX1, NOTCH3, PTCRA but not cMYC. NOTCH1/FBXW7 mutations were associated with TLX3 rearrangements, but were less frequently identified in TAL1- or LMO2-rearranged cases. NOTCH1-activating mutations were less frequently associated with mature T-cell developmental stage. Mutations were associated with a good initial in vivo prednisone response, but were not associated with a superior outcome in the DCOG and COALL cohorts. Comparing our data with other studies, we conclude that the prognostic significance for NOTCH1/FBXW7 mutations is not consistent and may depend on the treatment protocol given.
AuthorsL Zuurbier, I Homminga, V Calvert, M L te Winkel, J G C A M Buijs-Gladdines, C Kooi, W K Smits, E Sonneveld, A J P Veerman, W A Kamps, M Horstmann, E F Petricoin 3rd, R Pieters, J P P Meijerink
JournalLeukemia (Leukemia) Vol. 24 Issue 12 Pg. 2014-22 (Dec 2010) ISSN: 1476-5551 [Electronic] England
PMID20861909 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Homeodomain Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • TLX3 protein, human
  • Ubiquitin-Protein Ligases
  • Prednisone
Topics
  • Cell Cycle Proteins (genetics)
  • Child
  • F-Box Proteins (genetics)
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • Gene Rearrangement
  • Homeodomain Proteins (genetics)
  • Humans
  • Male
  • Mutation
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
  • Prednisone (therapeutic use)
  • Receptor, Notch1 (genetics)
  • Treatment Outcome
  • Ubiquitin-Protein Ligases (genetics)

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