Alteration of NOTCH1 in T-cell Acute Lymphoblastic Leukemia and Development of Target Therapeutic Agent
- Author:
Jung Hee RHO
1
;
In Sang JEON
Author Information
1. Department of Pediatrics, Graduate School of Medicine, Gachon University, Incheon, Korea. isjeon@gilhospital.com
- Publication Type:Review
- Keywords:
T-ALL;
NOTCH1;
Gamma-secretase inhibitor
- MeSH:
Amyloid Precursor Protein Secretases;
Child;
Gene Expression;
Genes, T-Cell Receptor;
Humans;
Incidence;
Oncogenes;
Precursor Cell Lymphoblastic Leukemia-Lymphoma;
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma;
T-Lymphocytes;
Transcription Factors
- From:Clinical Pediatric Hematology-Oncology
2014;21(1):1-8
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-15% of entire ALL in children. The outcome of T-ALL has been improved through the intensified therapeutic strategy, however, it is still a more aggressive disease. In T-ALL a couple of transcription factor oncogenes are known to be relocated to the juxtaposition of T-cell receptor genes, potent promoter, by chromosome translocation. However the incidence of each chimeric gene formation in T-ALL is less than 5% and their clinical significance as a prognostic marker is lacking. A decade ago it was identified that activating mutations in NOTCH1 in about 60% of T-ALL. After then, activating NOTCH1 mutations present in T-ALL have been extensively investigated with regard to understanding its molecular pathogenesis, its prognostic significance, and developing molecularly tailored novel agents. Small molecule gamma-secretase inhibitor, blocking a proteolytic step required for creation of a fragment of NOTCH intracellular domain which actually act as a controller of its target gene expression, was tried as a target therapeutic drug for T-ALL. Although outcome of this drug was not satisfactory, challenges have been launched to develop new drugs which specifically act on the aberrant behavior of mutated NOTCH1 in T-ALL.
