NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis.
OBJECTIVE
NOTCH signaling pathway is essential in T-cell development and NOTCH1 mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). To gain insight into its clinical significance, NOTCH1 mutation was investigated in 77 patients with T-ALL.


METHODS
Detection of NOTCH1 mutation was done using reverse transcription-PCR amplification and direct sequencing, and thereby compared according to the clinical/biological data of the patients.


RESULTS
Thirty-two mutations were identified in 29 patients (with dual mutations in 3 cases), involving not only the heterodimerization and proline/glutamic acid/serine/threonine domains as previously reported but also the transcription activation and ankyrin repeat domains revealed for the first time. These mutations were significantly associated with elevated WBC count at diagnosis and independently linked to short survival time. Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (< or = 18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy. NOTCH1 mutations could coexist with HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation on prognosis was potentiated by HOX11L2 but was attenuated by HOX11.


CONCLUSIONS
NOTCH1 mutation is an important prognostic marker in T-ALL and its predictive value could be even further increased if coevaluated with other T-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with oncogenic transcriptional factors on T-ALL pathogenesis.
Zhu
Yong-Mei
YM
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, China.
Zhao
Wei-Li
WL
Fu
Jian-Fei
JF
Shi
Jing-Yi
JY
Pan
Qin
Q
Hu
Jiong
J
Gao
Xiao-Dong
XD
Chen
Bing
B
Li
Jun-Min
JM
Xiong
Shu-Min
SM
Gu
Long-Jun
LJ
Tang
Jing-Yi
JY
Liang
Hui
H
Jiang
Hui
H
Xue
Yong-Quan
YQ
Shen
Zhi-Xiang
ZX
Chen
Zhu
Z
Chen
Sai-Juan
SJ
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008969:Molecular Sequence Data; D011237:Predictive Value of Tests; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016019:Survival Analysis
C497761:NOTCH1 protein, human; D051881:Receptor, Notch1