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Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children

Leukemia volume 19, pages 1841–1843 (2005)Cite this article

TO THE EDITOR

Notch signaling plays a key role in the cell fate decision at various differentiation branch points.1 In mammals, it has been well recognized that the deregulated activation of Notch signaling leads to tumor development.2 This concept is highlighted by a recent report demonstrating that as much as 60% of childhood T-cell acute lymphoblastic leukemia (T-ALL) has mutations in the Notch1 gene.3 The resulting amino-acid changes have been found in the heterodimerization (HD) domains at the C- and N-termini of the extracellular and transmembrane subunits (HDEC and HD™ domains), respectively, and the transcriptional activation (TA) and PEST domains at the cytoplasmic region of the transmembrane subunit. The former mutations are thought to reduce the affinity between the two subunits, which subsequently leads to ligand-independent γ-cleavage of the Notch1 transmembrane subunit and production of an activated Notch1 intracellular domain. In the latter, insertion or deletion mutations introduce a premature stop codon that results in truncation of the PEST domain, which eventually causes prolonged half-life of the cleaved Notch1 intracellular domain. Both mutations appear to result in activation of Notch signaling and initiate or develop leukemia.3 Extremely high frequency of activating mutations of the Notch1 gene gave us an idea that T-ALL is commonly dependent on abnormal Notch1 activation. Based on these findings, it has been postulated that γ-secretase inhibitors, which are considered as a treatment modality against Alzheimer's disease,4 could be useful as anti-T-ALL drugs.

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Acknowledgements

This work was supported in part by Grant-in-Aid for Scientific Research on Priority Areas, KAKENHI-17013022 (to SO) and KAKENHI-17390274 (to SC) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by Japan Health Sciences Foundation (to SC).

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Authors and Affiliations

  1. Department of Cell Therapy and Transplantation Medicine, University of Tokyo, Tokyo, Japan

    S-Y Lee, K Kumano, S Masuda & S Chiba

  2. Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan

    K Kumano, S Masuda, A Hangaishi, K Nakazaki, M Kurokawa, S Ogawa & S Chiba

  3. Department of Regeneration Medicine for Hematopoiesis, University of Tokyo, Tokyo, Japan

    S Ogawa

  4. Department of Pediatrics, University of Tokyo, Tokyo, Japan

    J Takita

  5. Department of Hematology and Oncology, Gunma Children's Medical Center, Gunma, Japan

    Y Hayashi

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  1. S-Y Lee
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  2. K Kumano
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  3. S Masuda
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Correspondence to S Chiba.

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Lee, SY., Kumano, K., Masuda, S. et al. Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia 19, 1841–1843 (2005). https://doi.org/10.1038/sj.leu.2403896

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