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.
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.
Zuurbier
L
L
Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands.
Homminga
I
I
Calvert
V
V
te Winkel
M L
ML
Buijs-Gladdines
J G C A M
JG
Kooi
C
C
Smits
W K
WK
Sonneveld
E
E
Veerman
A J P
AJ
Kamps
W A
WA
Horstmann
M
M
Petricoin
E F
EF
Pieters
R
R
Meijerink
J P P
JP
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*
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