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Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia

  • Progress in Hematology
  • Signaling and transcription in the development of leukemia
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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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Acknowledgments

This work was supported by grants from the National Institute of Health to W.S.P. (R01AI047833, P01CA119070) and a Leukemia and Lymphoma Society SCOR Award to W.S.P. H.L. was provided with an NIH-funded Institutional Research Training Grant (T32-DK07780) and a Fellow Award from the Lymphoma Research Foundation. M.Y.C. received a career development award from the NCI (K08 CA120544-01).

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The authors declare no relevant affiliations or financial involvement with any organizations.

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  1. Hudan Liu

    Present address: Tongji Medical College, School of Pharmacy, Huazhong University of Science and Technology, Room 402, 13 Hangkong Road, Wuhan, Hubei, 430030, People’s Republic of China

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Hudan Liu & Warren S. Pear

  2. Department of Hematology/Oncology, University of Michigan Cancer Center, Biomedical Science Research Building, Room 2043, 109 Zina Pitcher Place, Ann Arbor, MI, 48103, USA

    Mark Y. Chiang

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Liu, H., Chiang, M.Y. & Pear, W.S. Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia. Int J Hematol 94, 118–125 (2011). https://doi.org/10.1007/s12185-011-0899-3

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