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.
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Authors | L 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 |
Journal | Leukemia
(Leukemia)
Vol. 24
Issue 12
Pg. 2014-22
(Dec 2010)
ISSN: 1476-5551 [Electronic] England |
PMID | 20861909
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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