International E-publication: Publish Projects, Dissertation, Theses, Books, Souvenir, Conference Proceeding with ISBN.  International E-Bulletin: Information/News regarding: Academics and Research

Clinical Relevance of Notch1 in T-Cell Acute Lymphoblastic Leukaemia

Author Affiliations

  • 1Department of Molecular Oncology, Cancer Institute (WIA), Chennai, Tamilnadu, INDIA

Int. Res. J. Biological Sci., Volume 2, Issue (8), Pages 66-72, August,10 (2013)


Notch1 signalling is an essential event in the thymopoiesis. Activating Notch1 mutations are frequently seen in T-Acute Lymphoblastic Leukaemia (T-ALL). Notch1 is mainly involved in the T cell proliferation, differentiation and apoptosis. The mutations in the Notch1 have been reported in more than 50% of T-ALL cases. The aberrant Notch1 signalling has a prominent role in the biology of T-ALL. Activating mutations of Notch1 were clinically significant in the molecular pathogenesis of T-ALL. The Crucial role of Notch1 in T cell lineage commitment and in the making of T-ALL paves the way to study Notch1 as a therapeutic target in the T-ALL therapy. In this review, the role of Notch1 in T-ALL, its signalling mechanism, Notch1 mutations, its impact on the disease prognosis and its therapeutic significance has been discussed to reiterate Notch1 as a molecular marker in T-ALL.


  1. Andrew P. Weng, Adolfo A. Ferrando, Woojoong Lee, John P. Morris IV, Lewis B. Silverman, Cheryll Sanchez-Irizarry et al, Activating mutations of NOTCH1 in human T Cell Acute Lymphoblastic Leukemia, Science, 306, 269-271 (2004)
  2. Ma J. and Wu M., The indicative effect of Notch1 expression for the prognosis of T-cell acute lymphocytic leukaemia: a systematic review, Springer- Molecular Biology reports, 39, 6095-6100 (2012)
  3. Eric J. Allenspach, Ivan Maillard, Jon C. Aster and Warren S.Pear. Notch1 signalling in cancer, Cancer Biology and Therapy, 1, 466-476 (2002)
  4. Anthony Wei Shine Chi, Delineation of the cellular pathway and molecular mechanisms of Notch1-mediated early T lineage development, http://repository.upenn. edu/dissertations/AAI3462211 (2011)
  5. Jon C. Aster, Nick Bodnar, Lanwei Xu, Fredrick Karnell, John M. Milholland and Ivan Maillard, Notch1 Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation, Plos One, 10, 1-10 (2011)
  6. Wendy R. Gordon, Didem Vardar-Ulu, Sarah L'Heureux, Todd Ashworth, Michael J. Malecki et al., Effects of S1 Cleavage on the Structure, Surface Export, and Signalling Activity of Human Notch1 and Notch12, PLoS ONE, 4(8), 1-12 (2009)
  7. Emma R. Andersson, Rickard Sandberg and Urban Lendahl, Notch1 signaling: simplicity in design, versatility in function, Development, 138, 3593-3612 (2011)
  8. Jon C. Aster, Warren S., Pear and Stephen C. Blacklow, Notch1 Signalling in Leukemia, Annu.Rev. Pathol. Mech. Dis, 3, 587-613 (2008)
  9. Jennifer O. Neil, Jonathan Grim, Peter Strack, Sudhir rao, Deanne Tibbitts et al. FBW7 mutations in leukemic cells mediate NOTCH1 pathway activation and resistance to gamma secretase inhibitors, Jem, 204(8), 1813-1824 (2007)
  10. Zhang N., Fu Z., Linke S., Chicher J., Gorman J.J., Visk D., Haddad G.G., Poellinger L., Peet D.J., Powell F. Et Al., The Asparaginyl Hydroxylasefactor Inhibiting Hif-1alpha Is An Essential Regulator of Metabolism, Cell Metab., 11, 364-378 (2010)
  11. Andrew P., Weng John M. Millholland, Yumi Yashiro-Ohtani. Marie Laure Arcangeli, Arthur Lau, Carol Wai, Cristina del Bianco,c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma,Genes Dev.; 20, 2096-2109 (2006)
  12. Huden Liu, Mark Y. Chiang, Warren S. Pear, Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia, Int J Hematol, 94, 118-125 (2011)
  13. Ana Silva, Patrícia Y. Jotta, André B. Silveira, Daniel Ribeiro, Silvia R. Brandalise, J. Andrés Yunes, and João T. Barata, Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and g-secretase inhibitors, Haematologica, 95(4), 674-678 (2010)
  14. Iannis Aifantis, Tomas Vilimas, Silvia Buonamici, Notch1es, NFkBs and the Making of T cell Leukemia, Cell Cycle, 4, 403-406 (2007)
  15. Sudhir S. Rao, Jennifer O’Neil, Cole D. Liberator, James S. Hardwick,4 Xudong Dai,Theresa Zhang et al., Inhibition of NOTCH1 Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells, Cancer Res,69, 3060-3068 (2009)
  16. Casper Groth, Mark E. Fortini, Therapeutic approaches to modulating Notch1 signaling: Current challenges and future prospects, ELSEVIER, Seminars in Cell & Developmental Biology, 01(016), 1-8 (2012)
  17. Deangelo D., Stone R., Silverman L., Stock W., Attar E., Fearen I. et al., A phase I lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias, J Clin Oncol, ASCO Annual Meeting Proceedings part I.:24 (18S) (2006)
  18. Keersmaecker K.D., Lahortige I., Mentens N., Folens C., Van Neste L. and Bekaert S. et al., In vitrovalidation of g-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-all acute lymphoblastic leukemia, Haematologica 193, 533542 (2008)
  19. Teresa Palomero, Maria Luisa Sulis, Maria Cortina, Pedro J Real, Kelly Barnes, Maria Ciofani et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia, Nature Medicine, 13, 1203-1210 (2007)
  20. Paola Secchiero, Elisabetta Melloni, Maria Grazia di Iasio, Mario Tiribelli, Erika Rimondi, Federica Corallini, Valter Gattei, and Giorgio Zaul, Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism, Blood, 113(18), 4300-08 (2008)
  21. Silvia Rasi, Sara Monti, Valeria Spina and Robin Foa, Gianluca Gaidano and Davide Rossi, Analysis of NOTCH1 mutations in monoclonal B cell lymphocytosis, Doi: 10.3324/haematol..053090 (2011)
  22. Stephen Breit, Martin Stanulla, Thomas Flohr, Martin Schrappe, Wolf-Dieter Ludwig, Gabriele Tolle, et al.Activating NOTCH1mutations predict favourable early treatment response and long term outcome in child-hood precursor T-cell lymphoblastic leukemia, Blood, 12, 4956 (2005)
  23. Zweilder – Mckay P.A., Pear W.S. Notch1 and T cell malignancy, Seminar Cancer Biol, 14, 329-340 (2004)
  24. Myoung-Ja Park, Tomohiko Taki, Megumi Oda, Yasuhide Hayashi. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma, British Journal of hematology, 145(2), 198-206 (2009)
  25. Chunlan Lin, Haiteo Zheng, Chunyan wang etal., Mutations increased overexpression of Notch1 in T-cell acute lymphoblastic leukemia, Cancer Cell Int, 12,(2012)
  26. Vahid Asnafi, Agnes buzyn, Sandrine le Noir, Fredric Baldier et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favourable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study, Blood, 113(17), 3918-3924 (2008)
  27. Bhanushali Aparna A., Babu Suresh, Thangapandi Veera Raghavan, Pillai Renjith, Chheda Pratiksha, Das, Bibhu R., Mutations in the HD and PEST Domain of Notch1-1 Receptor in T-Cell Acute Lymphoblastic Leukaemia: Report of Novel Mutations From Indian Population, Oncology Research, 9(2), 99-104 (2010)
  28. Jenkinson S., Koo K., Mansour M.R., Goulden N., A Vora et al. Impact of NOTCH1/FBXW7 mutations on outcome in paediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003, Leukemia, 27, 41–47 (2013)
  29. Gannie Tzoneva, Adolfo A. Ferrando, Recent Advances on NOTCH1 Signaling in T-ALL, Springer, 360, 163-182 (2012)
  30. Valeria Tosello, Adolfo Ferrando, The Notch1 signalling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukaemia (T-ALL) and implication for therapy, Therapeutic Advances in Hematology (2013)