Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol.
OBJECTIVE
Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.


METHODS
NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome.


RESULTS
NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72).


CONCLUSIONS
NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.
Mansour
Marc R
MR
Department of Haematology, University College London, UCL Cancer Institute, WC1E 6BT, United Kingdom. m.mansour@ucl.ac.uk
Sulis
Maria L
ML
Duke
Veronique
V
Foroni
Letizia
L
Jenkinson
Sarah
S
Koo
Kenneth
K
Allen
Christopher G
CG
Gale
Rosemary E
RE
Buck
Georgina
G
Richards
Sue
S
Paietta
Elisabeth
E
Rowe
Jacob M
JM
Tallman
Martin S
MS
Goldstone
Anthony H
AH
Ferrando
Adolfo A
AA
Linch
David C
DC
D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000628:therapy*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D006113:United Kingdom; D055815:Young Adult
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases