An activating intragenic deletion in NOTCH1 in human T-ALL.
Blood
; 119(22): 5211-4, 2012 May 31.
Article
in En
| MEDLINE
| ID: mdl-22510873
ABSTRACT
Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5' portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the γ-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by γ-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Alleles
/
Receptor, Notch1
/
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/
Neoplasm Proteins
Type of study:
Clinical_trials
Limits:
Adult
/
Female
/
Humans
/
Male
Language:
En
Journal:
Blood
Year:
2012
Document type:
Article
Affiliation country:
United States