Clin Pediatr Hematol Oncol.  2014 Apr;21(1):1-8.

Alteration of NOTCH1 in T-cell Acute Lymphoblastic Leukemia and Development of Target Therapeutic Agent

• Rho JH
• Jeon IS

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.

Keyword

T-ALL; NOTCH1; Gamma-secretase inhibitor

MeSH Terms

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
Amyloid Precursor Protein Secretases
Transcription Factors