title: 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.
authors.affiliation: Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Zuurbier
authors.forename: I
authors.initials: I
authors.lastname: Homminga
authors.forename: V
authors.initials: V
authors.lastname: Calvert
authors.forename: M L
authors.initials: ML
authors.lastname: te Winkel
authors.forename: J G C A M
authors.initials: JG
authors.lastname: Buijs-Gladdines
authors.forename: C
authors.initials: C
authors.lastname: Kooi
authors.forename: W K
authors.initials: WK
authors.lastname: Smits
authors.forename: E
authors.initials: E
authors.lastname: Sonneveld
authors.forename: A J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: W A
authors.initials: WA
authors.lastname: Kamps
authors.forename: M
authors.initials: M
authors.lastname: Horstmann
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: J P P
authors.initials: JP
authors.lastname: Meijerink
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015321:Gene Rearrangement; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011241:Prednisone / Q000627:therapeutic use*; D051881:Receptor, Notch1 / Q000235:genetics*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D018398:Homeodomain Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C489494:TLX3 protein, human; D044767:Ubiquitin-Protein Ligases; D011241:Prednisone