NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study.
Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.
Asnafi
Vahid
V
Université Paris 5 Descartes and Assistance Publique Hôpitaux de Paris (AP-HP) and Hematology Department, Hôpital Necker-Enfants-Malades, Paris, France.
Buzyn
Agnès
A
Le Noir
Sandrine
S
Baleydier
Frédéric
F
Simon
Arnauld
A
Beldjord
Kheira
K
Reman
Oumedaly
O
Witz
Francis
F
Fagot
Thierry
T
Tavernier
Emmanuelle
E
Turlure
Pascal
P
Leguay
Thibaut
T
Huguet
Françoise
F
Vernant
Jean-Paul
JP
Daniel
Francis
F
Béné
Marie-Christine
MC
Ifrah
Norbert
N
Thomas
Xavier
X
Dombret
Hervé
H
Macintyre
Elizabeth
E
D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D012955:Societies, Medical; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases