NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL.
Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (P=0.003) and +12 as a sole cytogenetic abnormality (P=0.008). NOTCH1 mutations in +12 CLL associated with an approximately 2.4 fold increase in the risk of death, a significant shortening of survival (P<0.01) and proved to be an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL conferred a significantly worse survival compared to that of +12 CLL with del(13q) or +12 only. The overrepresentation of cell cycle/proliferation related genes of +12 CLL with NOTCH1 mutations suggests the biological contribution of NOTCH1 mutations to determine a poor outcome. NOTCH1 mutations refine the intermediate prognosis of +12 CLL.
Division of Hematology, Department of Cellular Biotechnologies and Haematology University, Sapienza Via Benevento 6, 00161 Rome, Italy. delgiudice@bce.uniroma1.it
Ilaria
I
Del Giudice
Davide
D
Rossi
Sabina
S
Chiaretti
Marilisa
M
Marinelli
Simona
S
Tavolaro
Sara
S
Gabrielli
Luca
L
Laurenti
Roberto
R
Marasca
Silvia
S
Rasi
Marco
M
Fangazio
Anna
A
Guarini
Gianluca
G
Gaidano
Robin
R
Foà
D000368:Aged; D002881:Chromosomes, Human, Pair 12; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D016019:Survival Analysis; D014158:Transcription, Genetic; D014314:Trisomy
D051881:Receptor, Notch1