期刊
LEUKEMIA
卷 24, 期 12, 页码 2014-2022出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2010.204
关键词
pediatric T-ALL; NOTCH1; FBXW7; TLX3; prednisone response; outcome
资金
- Stichting Kinderen Kankervrij (KiKa) [KiKa 2007-012, KiKa 2008-029]
- Dutch Cancer Society Dutch Cancer Society (KWF-EMCR) [2006-3500]
- German Jose Carreras Leukemia Foundation [SP 04/03]
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-kappa-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. Leukemia (2010) 24, 2014-2022; doi:10.1038/leu.2010.204; published online 23 September 2010
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