International Journal of Hematology

DOI: 10.1007/s12185-011-0899-3 Pages: 118-125

Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia

1. University of Pennsylvania, Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute

2. University of Michigan Cancer Center, Department of Hematology/Oncology

3. Huazhong University of Science and Technology, Tongji Medical College, School of Pharmacy

Correspondence to:
Mark Y. Chiang
Email: markchia@med.umich.edu

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Abstract

NOTCH1 plays a central role in T-cell development and, when aberrantly activated, in acute T-cell lymphoblastic leukemia (T-ALL). As a transmembrane receptor that is ultimately converted into a transcription factor, NOTCH1 directly activates a spectrum of target genes, which function to mediate NOTCH1 signaling in normal or transformed T cells. During physiologic T-cell development, NOTCH1 has important functions in cell fate determination, proliferation, survival and metabolism. Activating NOTCH1 mutations occur in more than half of human patients with T-ALL, suggesting an important role for aberrant NOTCH1 signaling in the pathogenesis of this disease. Inhibiting NOTCH1 signaling in patient-derived cell lines and murine T-ALLs leads to growth arrest and/or apoptosis suggesting that NOTCH1 inhibitors can improve T-ALL treatment. However, there are challenges to translate NOTCH1 inhibitors to the clinic because of toxicity and resistance. This review focuses on molecular mechanisms of oncogenic NOTCH1 signaling, molecular and functional analysis of NOTCH1 transcriptional targets in T-ALL, and recent advances in therapeutic targeting of NOTCH1.

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