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Notch Signaling in T-Cell Acute Lymphoblastic Leukemia and Other Hematologic Malignancies

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Targeting Notch in Cancer

Abstract

Notch is a highly conserved signaling pathway that is crucial for development and homeostasis of many normal tissues and cell types. Deregulated Notch signaling is associated with human disease in several different tissue contexts but is perhaps best characterized in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Activating mutations in the NOTCH1 gene and other elements of the Notch signaling pathway such as FBW7 result in increased Notch signaling intensity and/or duration and are acquired spontaneously at high frequency in primary human T-ALL and in experimentally derived mouse models of T-ALL. As well, enforced expression of activated NOTCH1 in normal hematopoietic progenitors promotes cellular transformation and leads to development of T-ALL-like disease in mice. Recent work has highlighted a role for the Notch pathway in other hematologic malignancies as well. While gain-of-function mutations in NOTCH receptors occur frequently in mature B-cell malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and splenic marginal zone lymphoma (SMZL), activation of the Notch pathway can also block tumor progression in myeloid malignancies, highlighting its highly versatile and context-dependent nature. In this chapter, we summarize the most recent findings regarding the pathogenic role of Notch signaling in various hematologic malignancies and current strategies to inhibit it therapeutically.

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References

  1. Wang, Y., Shao, L., Shi, S., et al. (2001). Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase. The Journal of Biological Chemistry, 276, 40338–40345.

    Article  CAS  PubMed  Google Scholar 

  2. Ju, B. G., Jeong, S., Bae, E., et al. (2000). Fringe forms a complex with Notch. Nature, 405, 191–195.

    Article  CAS  PubMed  Google Scholar 

  3. Lubman, O. Y., Ilagan, M. X., Kopan, R., et al. (2007). Quantitative dissection of the Notch:CSL interaction: Insights into the Notch-mediated transcriptional switch. Journal of Molecular Biology, 365, 577–589.

    Article  CAS  PubMed  Google Scholar 

  4. Shimizu, K., Chiba, S., Kumano, K., et al. (1999). Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods. The Journal of Biological Chemistry, 274, 32961–32969.

    Article  CAS  PubMed  Google Scholar 

  5. Ohishi, K., Katayama, N., Shiku, H., et al. (2003). Notch signalling in hematopoiesis. Seminars in Cell & Developmental Biology, 14, 143–150.

    Article  CAS  Google Scholar 

  6. Logeat, F., Bessia, C., Brou, C., et al. (1998). The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proceedings of the National Academy of Sciences of the United States of America, 95, 8108–8112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rand, M. D., Grimm, L. M., Artavanis-Tsakonas, S., et al. (2000). Calcium depletion dissociates and activates heterodimeric notch receptors. Molecular and Cellular Biology, 20, 1825–1835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sanchez-Irizarry, C., Carpenter, A. C., Weng, A. P., et al. (2004). Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Molecular and Cellular Biology, 24, 9265–9273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gordon, W. R., Vardar-Ulu, D., Histen, G., et al. (2007). Structural basis for autoinhibition of Notch. Nature Structural & Molecular Biology, 14, 295–300.

    Article  CAS  Google Scholar 

  10. Gordon, W. R., Roy, M., Vardar-Ulu, D., et al. (2009). Structure of the Notch1-negative regulatory region: Implications for normal activation and pathogenic signaling in T-ALL. Blood, 113, 4381–4390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. van Tetering, G., van Diest, P., Verlaan, I., et al. (2009). Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. The Journal of Biological Chemistry, 284, 31018–31027.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Bozkulak, E. C., & Weinmaster, G. (2009). Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Molecular and Cellular Biology, 29, 5679–5695.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gordon Wendy, R., Zimmerman, B., He, L., et al. (2015). Mechanical allostery: Evidence for a force requirement in the proteolytic activation of Notch. Developmental Cell, 33, 729–736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rechsteiner, M., & Rogers, S. W. (1996). PEST sequences and regulation by proteolysis. Trends in Biochemical Sciences, 21, 267–271.

    Article  CAS  PubMed  Google Scholar 

  15. Lai, E. C. (2002). Keeping a good pathway down: Transcriptional repression of Notch pathway target genes by CSL proteins. EMBO Reports, 3, 840–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liefke, R., Oswald, F., Alvarado, C., et al. (2010). Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex. Genes & Development, 24, 590–601.

    Article  CAS  Google Scholar 

  17. Oswald, F., Tauber, B., Dobner, T., et al. (2001). p300 acts as a transcriptional coactivator for mammalian notch-1. Molecular and Cellular Biology, 21, 7761–7774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wallberg, A. E., Pedersen, K., Lendahl, U., et al. (2002). p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Molecular and Cellular Biology, 22, 7812–7819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fryer, C. J., White, J. B., & Jones, K. A. (2004). Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Molecular Cell, 16, 509–520.

    Article  CAS  PubMed  Google Scholar 

  20. Oberg, C., Li, J., Pauley, A., et al. (2001). The notch intracellular domain is ubiquitinated and negatively regulated by the mammalian sel-10 homolog. The Journal of Biological Chemistry, 276, 35847–35853.

    Article  CAS  PubMed  Google Scholar 

  21. Ehebauer, M. T., Chirgadze, D. Y., Hayward, P., et al. (2005). High-resolution crystal structure of the human Notch 1 ankyrin domain. The Biochemical Journal, 392, 13–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nam, Y., Sliz, P., Song, L., et al. (2006). Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell, 124, 973–983.

    Article  CAS  PubMed  Google Scholar 

  23. Nam, Y., Sliz, P., Pear, W. S., et al. (2007). Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proceedings of the National Academy of Sciences of the United States of America, 104, 2103–2108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu, H., Chi, A. W., Arnett, K. L., et al. (2010). Notch dimerization is required for leukemogenesis and T-cell development. Genes & Development, 24, 2395–2407.

    Article  CAS  Google Scholar 

  25. Adler, S. H., Chiffoleau, E., Xu, L., et al. (2003). Notch signaling augments T cell responsiveness by enhancing CD25 expression. Journal of Immunology, 171, 2896–2903.

    Article  CAS  Google Scholar 

  26. Reizis, B., & Leder, P. (2002). Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes & Development, 16, 295–300.

    Article  CAS  Google Scholar 

  27. Ho, I. C., Tai, T. S., & Pai, S. Y. (2009). GATA3 and the T-cell lineage: Essential functions before and after T-helper-2-cell differentiation. Nature Reviews. Immunology, 9, 125–135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Borggrefe, T., & Oswald, F. (2009). The Notch signaling pathway: Transcriptional regulation at Notch target genes. Cellular and Molecular Life Sciences, 66, 1631–1646.

    Article  CAS  PubMed  Google Scholar 

  29. Grbavec, D., & Stifani, S. (1996). Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Biochemical and Biophysical Research Communications, 223, 701–705.

    Article  CAS  PubMed  Google Scholar 

  30. Fischer, A., & Gessler, M. (2007). Delta-Notch–and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Research, 35, 4583–4596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mukherjee, A., Veraksa, A., Bauer, A., et al. (2005). Regulation of Notch signalling by non-visual beta-arrestin. Nature Cell Biology, 7, 1191–1201.

    Article  PubMed  CAS  Google Scholar 

  32. Matsuno, K., Diederich, R. J., Go, M. J., et al. (1995). Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development, 121, 2633–2644.

    CAS  PubMed  Google Scholar 

  33. Lamar, E., Deblandre, G., Wettstein, D., et al. (2001). Nrarp is a novel intracellular component of the Notch signaling pathway. Genes & Development, 15, 1885–1899.

    Article  CAS  Google Scholar 

  34. Yun, T. J., & Bevan, M. J. (2003). Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: Multiple Notch1 signaling pathways involved in T cell development. Journal of Immunology, 170, 5834–5841.

    Article  CAS  Google Scholar 

  35. Weng, A. P., Millholland, J. M., Yashiro-Ohtani, Y., et al. (2006). c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes & Development, 20, 2096–2109.

    Article  CAS  Google Scholar 

  36. Sharma, V. M., Calvo, J. A., Draheim, K. M., et al. (2006). Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Molecular and Cellular Biology, 26, 8022–8031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, X., Gounari, F., Protopopov, A., et al. (2008a). Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1. The Journal of Experimental Medicine, 205, 2851–2861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Palomero, T., Lim, W. K., Odom, D. T., et al. (2006). NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proceedings of the National Academy of Sciences of the United States of America, 103, 18261–18266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Klinakis, A., Szabolcs, M., Politi, K., et al. (2006). Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proceedings of the National Academy of Sciences of the United States of America, 103, 9262–9267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yashiro-Ohtani, Y., Wang, H., Zang, C., et al. (2014). Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proceedings of the National Academy of Sciences of the United States of America, 111, E4946–E4953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Herranz, D., Ambesi-Impiombato, A., Palomero, T., et al. (2014). A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nature Medicine, 20, 1130–1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cohen, B., Shimizu, M., Izrailit, J., et al. (2010). Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer. Breast Cancer Research and Treatment, 123, 113–124.

    Article  CAS  PubMed  Google Scholar 

  43. Rangarajan, A., Talora, C., Okuyama, R., et al. (2001). Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. The EMBO Journal, 20, 3427–3436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kumano, K., Chiba, S., Kunisato, A., et al. (2003). Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity, 18, 699–711.

    Article  CAS  PubMed  Google Scholar 

  45. Hadland, B. K., Huppert, S. S., Kanungo, J., et al. (2004). A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood, 104, 3097–3105.

    Article  CAS  PubMed  Google Scholar 

  46. Gerhardt, D. M., Pajcini, K. V., D’Altri, T., et al. (2014). The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes & Development, 28, 576–593.

    Article  CAS  Google Scholar 

  47. Stier, S., Cheng, T., Dombkowski, D., et al. (2002). Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood, 99, 2369–2378.

    Article  CAS  PubMed  Google Scholar 

  48. Varnum-Finney, B., Wu, L., Yu, M., et al. (2000). Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. Journal of Cell Science, 113(Pt 23), 4313–4318.

    CAS  PubMed  Google Scholar 

  49. Maillard, I., Koch, U., Dumortier, A., et al. (2008a). Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell, 2, 356–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Radtke, F., Wilson, A., Stark, G., et al. (1999). Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity, 10, 547–558.

    Article  CAS  PubMed  Google Scholar 

  51. Han, H., Tanigaki, K., Yamamoto, N., et al. (2002). Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. International Immunology, 14, 637–645.

    Article  CAS  PubMed  Google Scholar 

  52. Pui, J. C., Allman, D., Xu, L., et al. (1999). Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity, 11, 299–308.

    Article  CAS  PubMed  Google Scholar 

  53. Schmitt, T. M., & Zuniga-Pflucker, J. C. (2002). Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity, 17, 749–756.

    Article  CAS  PubMed  Google Scholar 

  54. Mohtashami, M., Shah, D. K., Nakase, H., et al. (2010). Direct comparison of Dll1- and Dll4-mediated Notch activation levels shows differential lymphomyeloid lineage commitment outcomes. Journal of Immunology, 185, 867–876.

    Article  CAS  Google Scholar 

  55. Hozumi, K., Mailhos, C., Negishi, N., et al. (2008). Delta-like 4 is indispensable in thymic environment specific for T cell development. The Journal of Experimental Medicine, 205, 2507–2513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Koch, U., Fiorini, E., Benedito, R., et al. (2008). Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. The Journal of Experimental Medicine, 205, 2515–2523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hozumi, K., Negishi, N., Suzuki, D., et al. (2004). Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nature Immunology, 5, 638–644.

    Article  CAS  PubMed  Google Scholar 

  58. Wolfer, A., Wilson, A., Nemir, M., et al. (2002). Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. Immunity, 16, 869–879.

    Article  CAS  PubMed  Google Scholar 

  59. Wolfer, A., Bakker, T., Wilson, A., et al. (2001). Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development. Nature Immunology, 2, 235–241.

    Article  CAS  PubMed  Google Scholar 

  60. Robey, E., Chang, D., Itano, A., et al. (1996). An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell, 87, 483–492.

    Article  CAS  PubMed  Google Scholar 

  61. Tu, L., Fang, T. C., Artis, D., et al. (2005). Notch signaling is an important regulator of type 2 immunity. The Journal of Experimental Medicine, 202, 1037–1042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ellisen, L. W., Bird, J., West, D. C., et al. (1991). TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell, 66, 649–661.

    Article  CAS  PubMed  Google Scholar 

  63. Girard, L., Hanna, Z., Beaulieu, N., et al. (1996). Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis. Genes & Development, 10, 1930–1944.

    Article  CAS  Google Scholar 

  64. Shen, H., Suzuki, T., Munroe, D. J., et al. (2003). Common sites of retroviral integration in mouse hematopoietic tumors identified by high-throughput, single nucleotide polymorphism-based mapping and bacterial artificial chromosome hybridization. Journal of Virology, 77, 1584–1588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Howard, G., Eiges, R., Gaudet, F., et al. (2008). Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene, 27, 404–408.

    Article  CAS  PubMed  Google Scholar 

  66. Hoemann, C. D., Beaulieu, N., Girard, L., et al. (2000). Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice. Molecular and Cellular Biology, 20, 3831–3842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aster, J., Pear, W., Hasserjian, R., et al. (1994). Functional analysis of the TAN-1 gene, a human homolog of Drosophila notch. Cold Spring Harbor Symposia on Quantitative Biology, 59, 125–136.

    Article  CAS  PubMed  Google Scholar 

  68. Pear, W. S., Aster, J. C., Scott, M. L., et al. (1996). Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. The Journal of Experimental Medicine, 183, 2283–2291.

    Article  CAS  PubMed  Google Scholar 

  69. Campese, A. F., Garbe, A. I., Zhang, F., et al. (2006). Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood, 108, 305–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bellavia, D., Campese, A. F., Alesse, E., et al. (2000). Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice. The EMBO Journal, 19, 3337–3348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Beverly, L. J., & Capobianco, A. J. (2003). Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. Cancer Cell, 3, 551–564.

    Article  CAS  PubMed  Google Scholar 

  72. Chen, J., Jette, C., Kanki, J. P., et al. (2007). NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia, 21, 462–471.

    Article  PubMed  CAS  Google Scholar 

  73. Chiang, M. Y., Xu, L., Shestova, O., et al. (2008). Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. The Journal of Clinical Investigation, 118, 3181–3194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Aster, J. C., Xu, L., Karnell, F. G., et al. (2000). Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by Notch1. Molecular and Cellular Biology, 20, 7505–7515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Aster, J. C., Bodnar, N., Xu, L., et al. (2011). Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. PLoS One, 6, e25645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Weng, A. P., Nam, Y., Wolfe, M. S., et al. (2003). Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Molecular and Cellular Biology, 23, 655–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wu, Y., Cain-Hom, C., Choy, L., et al. (2010a). Therapeutic antibody targeting of individual Notch receptors. Nature, 464, 1052–1057.

    Article  CAS  PubMed  Google Scholar 

  78. Weng, A. P., Ferrando, A. A., Lee, W., et al. (2004a). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 306, 269–271.

    Article  CAS  PubMed  Google Scholar 

  79. Mansour, M. R., Sulis, M. L., Duke, V., et al. (2009a). Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. Journal of Clinical Oncology, 27, 4352–4356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Asnafi, V., Buzyn, A., Le Noir, S., et al. (2009). NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): A Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood, 113, 3918–3924.

    Article  CAS  PubMed  Google Scholar 

  81. Zhu, Y. M., Zhao, W. L., Fu, J. F., et al. (2006). NOTCH1 mutations in T-cell acute lymphoblastic leukemia: Prognostic significance and implication in multifactorial leukemogenesis. Clinical Cancer Research, 12, 3043–3049.

    Article  CAS  PubMed  Google Scholar 

  82. Park, M. J., Taki, T., Oda, M., et al. (2009). FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. British Journal of Haematology, 145, 198–206.

    Article  CAS  PubMed  Google Scholar 

  83. van Grotel, M., Meijerink, J. P., Beverloo, H. B., et al. (2006). The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: A retrospective study of patients treated according to DCOG or COALL protocols. Haematologica, 91, 1212–1221.

    PubMed  Google Scholar 

  84. Breit, S., Stanulla, M., Flohr, T., et al. (2006). Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood, 108, 1151–1157.

    Article  CAS  PubMed  Google Scholar 

  85. Larson Gedman, A., Chen, Q., Kugel Desmoulin, S., et al. (2009). The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: A report from the Children’s Oncology Group. Leukemia, 23, 1417–1425.

    Article  CAS  PubMed  Google Scholar 

  86. Zhang, J., Ding, L., Holmfeldt, L., et al. (2012). The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature, 481, 157–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Neumann, M., Vosberg, S., Schlee, C., et al. (2015). Mutational spectrum of adult T-ALL. Oncotarget, 6, 2754–2766.

    Article  PubMed  Google Scholar 

  88. Homminga, I., Pieters, R., Langerak, A. W., et al. (2011). Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell, 19, 484–497.

    Article  CAS  PubMed  Google Scholar 

  89. Fabbri, G., Rasi, S., Rossi, D., et al. (2011). Analysis of the chronic lymphocytic leukemia coding genome: Role of NOTCH1 mutational activation. The Journal of Experimental Medicine, 208, 1389–1401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fabbri, G., Khiabanian, H., Holmes, A. B., et al. (2013). Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. The Journal of Experimental Medicine, 210, 2273–2288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Puente, X. S., Pinyol, M., Quesada, V., et al. (2011). Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature, 475, 101–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Andersson, E. R., Sandberg, R., & Lendahl, U. (2011). Notch signaling: Simplicity in design, versatility in function. Development, 138, 3593–3612.

    Article  CAS  PubMed  Google Scholar 

  93. Sportoletti, P., Baldoni, S., Del Papa, B., et al. (2014). A revised NOTCH1 mutation frequency still impacts survival while the allele burden predicts early progression in chronic lymphocytic leukemia. Leukemia, 28, 436–439.

    Article  CAS  PubMed  Google Scholar 

  94. Kridel, R., Meissner, B., Rogic, S., et al. (2012). Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood, 119, 1963–1971.

    Article  CAS  PubMed  Google Scholar 

  95. Beà, S., Valdés-Mas, R., Navarro, A., et al. (2013). Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proceedings of the National Academy of Sciences, 110, 18250–18255.

    Article  Google Scholar 

  96. Rossi, D., Trifonov, V., Fangazio, M., et al. (2012). The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. The Journal of Experimental Medicine, 209, 1537–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kiel, M. J., Velusamy, T., Betz, B. L., et al. (2012). Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. The Journal of Experimental Medicine, 209, 1553–1565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee, S. Y., Kumano, K., Nakazaki, K., et al. (2009). Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Science, 100, 920–926.

    Article  CAS  PubMed  Google Scholar 

  99. Malecki, M. J., Sanchez-Irizarry, C., Mitchell, J. L., et al. (2006). Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Molecular and Cellular Biology, 26, 4642–4651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sulis, M. L., Williams, O., Palomero, T., et al. (2008). NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood, 112, 733–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. O’Neil, J., Grim, J., Strack, P., et al. (2007a). FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors. The Journal of Experimental Medicine, 204, 1813–1824.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Thompson, B. J., Buonamici, S., Sulis, M. L., et al. (2007a). The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. The Journal of Experimental Medicine, 204, 1825–1835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chiang, M. Y., Xu, M. L., Histen, G., et al. (2006). Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Molecular and Cellular Biology, 26, 6261–6271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Welcker, M., Orian, A., Jin, J., et al. (2004a). The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proceedings of the National Academy of Sciences of the United States of America, 101, 9085–9090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Onoyama, I., Tsunematsu, R., Matsumoto, A., et al. (2007). Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. The Journal of Experimental Medicine, 204, 2875–2888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Malyukova, A., Dohda, T., von der Lehr, N., et al. (2007). The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Research, 67, 5611–5616.

    Article  CAS  PubMed  Google Scholar 

  107. King, B., Trimarchi, T., Reavie, L., et al. (2013a). The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell, 153, 1552–1566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Welcker, M., Orian, A., Grim, J. E., et al. (2004b). A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Current Biology, 14, 1852–1857.

    Article  CAS  PubMed  Google Scholar 

  109. Mantha, S., Ward, M., McCafferty, J., et al. (2007). Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant plastic/+ mice. Leukemia Research, 31, 321–327.

    Article  CAS  PubMed  Google Scholar 

  110. Reschly, E. J., Spaulding, C., Vilimas, T., et al. (2006). Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms. Blood, 107, 4115–4121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Maser, R. S., Choudhury, B., Campbell, P. J., et al. (2007). Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature, 447, 966–971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. O’Neil, J., Calvo, J., McKenna, K., et al. (2006). Activating Notch1 mutations in mouse models of T-ALL. Blood, 107, 781–785.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Lin, Y. W., Nichols, R. A., Letterio, J. J., et al. (2006). Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma. Blood, 107, 2540–2543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dumortier, A., Jeannet, R., Kirstetter, P., et al. (2006). Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice. Molecular and Cellular Biology, 26, 209–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tsuji, H., Ishii-Ohba, H., Ukai, H., et al. (2003). Radiation-induced deletions in the 5’ end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. Carcinogenesis, 24, 1257–1268.

    Article  CAS  PubMed  Google Scholar 

  116. Ashworth, T. D., Pear, W. S., Chiang, M. Y., et al. (2010). Deletion-based mechanisms of Notch1 activation in T-ALL: Key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood, 116, 5455–5464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kox, C., Zimmermann, M., Stanulla, M., et al. (2010). The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia, 24, 2005–2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Clappier, E., Collette, S., Grardel, N., et al. (2010). NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia, 24, 2023–2031.

    Article  CAS  PubMed  Google Scholar 

  119. Zuurbier, L., Homminga, I., Calvert, V., et al. (2010). NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia, 24, 2014–2022.

    Article  CAS  PubMed  Google Scholar 

  120. Real, P. J., Tosello, V., Palomero, T., et al. (2009a). [gamma]-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nature Medicine, 15, 50–58.

    Article  CAS  PubMed  Google Scholar 

  121. Bellavia, D., Campese, A. F., Checquolo, S., et al. (2002). Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proceedings of the National Academy of Sciences of the United States of America, 99, 3788–3793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Felli, M. P., Vacca, A., Calce, A., et al. (2005). PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene, 24, 992–1000.

    Article  CAS  PubMed  Google Scholar 

  123. Jeannet, R., Mastio, J., Macias-Garcia, A., et al. (2010). Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL. Blood, 116, 5443–5454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Palomero, T., Sulis, M. L., Cortina, M., et al. (2007). Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nature Medicine, 13, 1203–1210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gonzalez-Garcia, S., Garcia-Peydro, M., Martin-Gayo, E., et al. (2009). CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia. The Journal of Experimental Medicine, 206, 779–791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Barata, J. T., Silva, A., Brandao, J. G., et al. (2004). Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. The Journal of Experimental Medicine, 200, 659–669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Medyouf, H., Gusscott, S., Wang, H., et al. (2011a). High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. The Journal of Experimental Medicine, 208, 1809–1822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Correia, N. C., Gírio, A., Antunes, I., et al. (2014). The multiple layers of non-genetic regulation of PTEN tumour suppressor activity. European Journal of Cancer, 50, 216–225.

    Article  CAS  PubMed  Google Scholar 

  129. Silva, A., Yunes, J. A., Cardoso, B. A., et al. (2008). PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. The Journal of Clinical Investigation, 118, 3762–3774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Herranz, D., Ambesi-Impiombato, A., Sudderth, J., et al. (2015). Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nature Medicine, 21, 1182–1189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Medyouf, H., Gao, X., Armstrong, F., et al. (2010). Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss. Blood, 115, 1175–1184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Vilimas, T., Mascarenhas, J., Palomero, T., et al. (2007a). Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nature Medicine, 13, 70–77.

    Article  CAS  PubMed  Google Scholar 

  133. Oswald, F., Liptay, S., Adler, G., et al. (1998). NF-kappaB2 is a putative target gene of activated Notch-1 via RBP- Jkappa. Molecular and Cellular Biology, 18, 2077–2088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Vilimas, T., Mascarenhas, J., Palomero, T., et al. (2007b). Targeting the NF-[kappa]B signaling pathway in Notch1-induced T-cell leukemia. Nature Medicine, 13, 70–77.

    Article  CAS  PubMed  Google Scholar 

  135. Shin, H. M., Minter, L. M., Cho, O. H., et al. (2006). Notch1 augments NF-κB activity by facilitating its nuclear retention. The EMBO Journal, 25, 129–138.

    Article  CAS  PubMed  Google Scholar 

  136. Espinosa, L., Cathelin, S., D’Altri, T., et al. (2010). The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia. Cancer Cell, 18, 268–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Clarke, M. F., Dick, J. E., Dirks, P. B., et al. (2006). Cancer stem cells--perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Research, 66, 9339–9344.

    Article  CAS  PubMed  Google Scholar 

  138. Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3, 730–737.

    Article  CAS  PubMed  Google Scholar 

  139. Cox, C. V., Martin, H. M., Kearns, P. R., et al. (2007). Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia. Blood, 109, 674–682.

    Article  CAS  PubMed  Google Scholar 

  140. Chiu, P. P., Jiang, H., & Dick, J. E. (2010). Leukemia-initiating cells in human T-lymphoblastic leukemia exhibit glucocorticoid resistance. Blood, 116, 5268–5279.

    Article  CAS  PubMed  Google Scholar 

  141. Gerby, B., Clappier, E., Armstrong, F., et al. (2011). Expression of CD34 and CD7 on human T-cell acute lymphoblastic leukemia discriminates functionally heterogeneous cell populations. Leukemia, 25, 1249–1258.

    Article  CAS  PubMed  Google Scholar 

  142. Guo, W., Lasky, J. L., Chang, C. J., et al. (2008). Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature, 453, 529–533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Tremblay, M., Tremblay, C. S., Herblot, S., et al. (2010). Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes. Genes & Development, 24, 1093–1105.

    Article  CAS  Google Scholar 

  144. Giambra, V., Jenkins, C. R., Wang, H., et al. (2012a). NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-theta and reactive oxygen species. Nature Medicine, 18, 1693–1698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tatarek, J., Cullion, K., Ashworth, T., et al. (2011). Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood, 118, 1579–1590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Giambra, V., Jenkins, C. E., Lam, S. H., et al. (2015). Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling. Blood, 125, 3917–3927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chiang, M. Y., Shestova, O., Xu, L., et al. (2013). Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells. Blood, 121, 905–917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Armstrong, F., Brunet de la Grange, P., Gerby, B., et al. (2009). NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood, 113, 1730–1740.

    Article  CAS  PubMed  Google Scholar 

  149. Giambra, V., Jenkins, C. R., Wang, H., et al. (2012b). NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species. Nature Medicine, 18, 1693–1698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ma, W., Gutierrez, A., Goff, D. J., et al. (2012). NOTCH1 signaling promotes human T-cell acute lymphoblastic leukemia initiating cell regeneration in supportive niches. PLoS One, 7, e39725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Giambra, V., Gusscott, S., Gracias, D., et al. (2018). Epigenetic restoration of fetal-like IGF1 signaling inhibits leukemia stem cell activity. Cell Stem Cell, 23, 714–726. https://doi.org/10.1016/j.stem.2018.08.018.

    Article  PubMed  CAS  Google Scholar 

  152. Roderick, J. E., Tesell, J., Shultz, L. D., et al. (2014). c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood, 123, 1040–1050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tanigaki, K., Han, H., Yamamoto, N., et al. (2002). Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nature Immunology, 3, 443–450.

    Article  CAS  PubMed  Google Scholar 

  154. Saito, T., Chiba, S., Ichikawa, M., et al. (2003). Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity, 18, 675–685.

    Article  CAS  PubMed  Google Scholar 

  155. Wu, L., Maillard, I., Nakamura, M., et al. (2007). The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. Blood, 110, 3618–3623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Oyama, T., Harigaya, K., Muradil, A., et al. (2007). Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104, 9764–9769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Song, R., Kim, Y. W., Koo, B. K., et al. (2008). Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development. The Journal of Experimental Medicine, 205, 2525–2536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gibb, D. R., El Shikh, M., Kang, D. J., et al. (2010). ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. The Journal of Experimental Medicine, 207, 623–635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wendorff, A. A., Koch, U., Wunderlich, F. T., et al. (2010). Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity, 33, 671–684.

    Article  CAS  PubMed  Google Scholar 

  160. Zweidler-McKay, P. A., He, Y., Xu, L., et al. (2005). Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood, 106, 3898–3906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kuang, S. Q., Fang, Z., Zweidler-McKay, P. A., et al. (2013). Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia. PLoS One, 8, e61807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hamblin, T. J., Davis, Z., Gardiner, A., et al. (1999). Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood, 94, 1848–1854.

    CAS  PubMed  Google Scholar 

  163. Hubmann, R., Schwarzmeier, J. D., Shehata, M., et al. (2002). Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood, 99, 3742–3747.

    Article  CAS  PubMed  Google Scholar 

  164. Rosati, E., Sabatini, R., Rampino, G., et al. (2009). Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood, 113, 856–865.

    Article  CAS  PubMed  Google Scholar 

  165. Balatti, V., Bottoni, A., Palamarchuk, A., et al. (2012). NOTCH1 mutations in CLL associated with trisomy 12. Blood, 119, 329–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Del Giudice, I., Rossi, D., Chiaretti, S., et al. (2012). NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica, 97, 437–441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Nadeu, F., Delgado, J., Royo, C., et al. (2016). Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood, 127, 2122–2130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Rossi, D., Rasi, S., Fabbri, G., et al. (2012). Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood, 119(2), 521–529.

    Article  PubMed  CAS  Google Scholar 

  169. Puente, X. S., Bea, S., Valdes-Mas, R., et al. (2015). Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature, 526, 519–524.

    Article  CAS  PubMed  Google Scholar 

  170. Kluk, M. J., Ashworth, T., Wang, H., et al. (2013). Gauging NOTCH1 activation in cancer using immunohistochemistry. PLoS One, 8, e67306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Onaindia, A., Gomez, S., Piris-Villaespesa, M., et al. (2014). Chronic lymphocytic leukemia cells in lymph nodes show frequent NOTCH1 activation. Haematologica, 100, e200–e203.

    Article  PubMed  CAS  Google Scholar 

  172. Arruga, F., Gizdic, B., Serra, S., et al. (2014). Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia, 28, 1060–1070.

    Article  CAS  PubMed  Google Scholar 

  173. Jares, P., Colomer, D., & Campo, E. (2007). Genetic and molecular pathogenesis of mantle cell lymphoma: Perspectives for new targeted therapeutics. Nature Reviews. Cancer, 7, 750–762.

    Article  CAS  PubMed  Google Scholar 

  174. Salido, M., Baró, C., Oscier, D., et al. (2010). Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: A multicenter study of the Splenic B-Cell Lymphoma Group. Blood, 116, 1479–1488.

    Article  CAS  PubMed  Google Scholar 

  175. Rossi, D., Deaglio, S., Dominguez-Sola, D., et al. (2011). Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma. Blood, 118, 4930–4934.

    Article  PubMed  Google Scholar 

  176. Arcaini, L., Paulli, M., Boveri, E., et al. (2004). Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer, 100, 107–115.

    Article  PubMed  Google Scholar 

  177. Hermine, O., Lefrère, F., Bronowicki, J.-P., et al. (2002). Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. New England Journal of Medicine, 347, 89–94.

    Article  CAS  PubMed  Google Scholar 

  178. Link, B. K., Maurer, M. J., Nowakowski, G. S., et al. (2013). Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: A report from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource. Journal of Clinical Oncology, 31, 3272–3278.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Martinez, D., Royo, C., Castillo, P., et al. (2013). Recurrent mutations Of NOTCH genes in follicular lymphoma. Blood, 122, 4253–4253.

    Article  CAS  Google Scholar 

  180. Arcaini, L., Rossi, D., Lucioni, M., et al. (2015). The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection. Haematologica, 100, 246–252.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Jundt, F., Probsting, K. S., Anagnostopoulos, I., et al. (2004). Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood, 103, 3511–3515.

    Article  CAS  PubMed  Google Scholar 

  182. Houde, C., Li, Y., Song, L., et al. (2004). Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood, 104, 3697–3704.

    Article  CAS  PubMed  Google Scholar 

  183. Mirandola, L., Apicella, L., Colombo, M., et al. (2013). Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1. Leukemia, 27, 1558+.

    Article  CAS  PubMed  Google Scholar 

  184. Nefedova, Y., Sullivan, D. M., Bolick, S. C., et al. (2008a). Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood, 111, 2220–2229.

    Article  CAS  PubMed  Google Scholar 

  185. Kanzler, H., Küppers, R., Hansmann, M. L., et al. (1996). Hodgkin and Reed-Sternberg cells in Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. The Journal of Experimental Medicine, 184, 1495–1505.

    Article  CAS  PubMed  Google Scholar 

  186. Jundt, F., Anagnostopoulos, I., Forster, R., et al. (2002). Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood, 99, 3398–3403.

    Article  CAS  PubMed  Google Scholar 

  187. Skrtic, A., Korac, P., Kristo, D. R., et al. (2010). Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance. Human Pathology, 41, 1702–1710.

    Article  CAS  PubMed  Google Scholar 

  188. Schwarzer, R., Dorken, B., & Jundt, F. (2012). Notch is an essential upstream regulator of NF-kappaB and is relevant for survival of Hodgkin and Reed-Sternberg cells. Leukemia, 26, 806–813.

    Article  CAS  PubMed  Google Scholar 

  189. Bigas, A., Martin, D. I., & Milner, L. A. (1998). Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Molecular and Cellular Biology, 18, 2324–2333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Milner, L. A., Bigas, A., Kopan, R., et al. (1996). Inhibition of granulocytic differentiation by mNotch1. Proceedings of the National Academy of Sciences of the United States of America, 93, 13014–13019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ohishi, K., Varnum-Finney, B., Serda, R. E., et al. (2001). The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells. Blood, 98, 1402–1407.

    Article  CAS  PubMed  Google Scholar 

  192. Schroeder, T., Kohlhof, H., Rieber, N., et al. (2003). Notch signaling induces multilineage myeloid differentiation and up-regulates PU.1 expression. Journal of Immunology, 170, 5538–5548.

    Article  CAS  Google Scholar 

  193. Mercher, T., Cornejo, M. G., Sears, C., et al. (2008). Notch signaling specifies megakaryocyte development from hematopoietic stem cells. Cell Stem Cell, 3, 314–326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Poirault-Chassac, S., Six, E., Catelain, C., et al. (2010). Notch/Delta4 signaling inhibits human megakaryocytic terminal differentiation. Blood, 116, 5670–5678.

    Article  CAS  PubMed  Google Scholar 

  195. Chiaramonte, R., Basile, A., Tassi, E., et al. (2005). A wide role for NOTCH1 signaling in acute leukemia. Cancer Letters, 219, 113–120.

    Article  CAS  PubMed  Google Scholar 

  196. Tohda, S., & Nara, N. (2001). Expression of Notch1 and Jagged1 proteins in acute myeloid leukemia cells. Leukemia & Lymphoma, 42, 467–472.

    Article  CAS  Google Scholar 

  197. Tohda, S., Kogoshi, H., Murakami, N., et al. (2005). Diverse effects of the Notch ligands Jagged1 and Delta1 on the growth and differentiation of primary acute myeloblastic leukemia cells. Experimental Hematology, 33, 558–563.

    Article  CAS  PubMed  Google Scholar 

  198. Tohda, S., Sakano, S., Ohsawa, M., et al. (2002). A novel cell line derived from de novo acute myeloblastic leukaemia with trilineage myelodysplasia which proliferates in response to a Notch ligand, Delta-1 protein. British Journal of Haematology, 117, 373–378.

    Article  CAS  PubMed  Google Scholar 

  199. Tohda, S., Murata-Ohsawa, M., Sakano, S., et al. (2003). Notch ligands, Delta-1 and Delta-4 suppress the self-renewal capacity and long-term growth of two myeloblastic leukemia cell lines. International Journal of Oncology, 22, 1073–1079.

    CAS  PubMed  Google Scholar 

  200. Kannan, S., Sutphin, R. M., Hall, M. G., et al. (2013). Notch activation inhibits AML growth and survival: A potential therapeutic approach. The Journal of Experimental Medicine, 210, 321–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Lobry, C., Ntziachristos, P., Ndiaye-Lobry, D., et al. (2013). Notch pathway activation targets AML-initiating cell homeostasis and differentiation. The Journal of Experimental Medicine, 210, 301–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Tian, C., Yu, Y., Jia, Y., et al. (2015). HES1 activation suppresses proliferation of leukemia cells in acute myeloid leukemia. Annals of Hematology, 94, 1477–1483.

    Article  CAS  PubMed  Google Scholar 

  203. Kato, T., Sakata-Yanagimoto, M., Nishikii, H., et al. (2015). Hes1 suppresses acute myeloid leukemia development through FLT3 repression. Leukemia, 29, 576–585.

    Article  CAS  PubMed  Google Scholar 

  204. Klinakis, A., Lobry, C., Abdel-Wahab, O., et al. (2011). A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature, 473, 230–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Evin, G., Sernee, M. F., & Masters, C. L. (2006). Inhibition of gamma-secretase as a therapeutic intervention for Alzheimer’s disease: Prospects, limitations and strategies. CNS Drugs, 20, 351–372.

    Article  CAS  PubMed  Google Scholar 

  206. Luistro, L., He, W., Smith, M., et al. (2009). Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Research, 69, 7672–7680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Kolb, E. A., Gorlick, R., Keir, S. T., et al. (2012). Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a gamma-secretase inhibitor targeting notch signaling. Pediatric Blood & Cancer, 58, 815–818.

    Article  Google Scholar 

  208. Tammam, J., Ware, C., Efferson, C., et al. (2009). Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. British Journal of Pharmacology, 158, 1183–1195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. DeAngelo, D., Stone, R., Silverman, L., et al. (2006). A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I, 24, 6585.

    Google Scholar 

  210. Riccio, O., van Gijn, M. E., Bezdek, A. C., et al. (2008). Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Reports, 9, 377–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. van Es, J. H., van Gijn, M. E., Riccio, O., et al. (2005). Notch/[gamma]-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature, 435, 959–963.

    Article  PubMed  CAS  Google Scholar 

  212. Moellering, R. E., Cornejo, M., Davis, T. N., et al. (2009). Direct inhibition of the NOTCH transcription factor complex. Nature, 462, 182–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Maillard, I., Weng, A. P., Carpenter, A. C., et al. (2004). Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood, 104, 1696–1702.

    Article  CAS  PubMed  Google Scholar 

  214. Aste-Amezaga, M., Zhang, N., Lineberger, J. E., et al. (2010). Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One, 5, e9094.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Li, K., Li, Y., Wu, W., et al. (2008b). Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. The Journal of Biological Chemistry, 283, 8046–8054.

    Article  CAS  PubMed  Google Scholar 

  216. Agnusdei, V., Minuzzo, S., Frasson, C., et al. (2014). Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia, 28, 278–288.

    Article  CAS  PubMed  Google Scholar 

  217. Yen, W. C., Fischer, M. M., Axelrod, F., et al. (2015). Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clinical Cancer Research, 21, 2084–2095.

    Article  CAS  PubMed  Google Scholar 

  218. Ridgway, J., Zhang, G., Wu, Y., et al. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature, 444, 1083–1087.

    Article  CAS  PubMed  Google Scholar 

  219. Noguera-Troise, I., Daly, C., Papadopoulos, N. J., et al. (2006). Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature, 444, 1032–1037.

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. *Catherine Hoofd and Vincenzo Giambra contributed equally to this work.

Authors and Affiliations

  1. Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada

    Catherine Hoofd, Vincenzo Giambra & Andrew P. Weng

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  1. Catherine Hoofd
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  2. Vincenzo Giambra
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  3. Andrew P. Weng
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Correspondence to Andrew P. Weng .

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Editors and Affiliations

  1. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Lucio Miele

  2. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Spyros Artavanis-Tsakonas

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Hoofd, C., Giambra, V., Weng, A.P. (2018). Notch Signaling in T-Cell Acute Lymphoblastic Leukemia and Other Hematologic Malignancies. In: Miele, L., Artavanis-Tsakonas, S. (eds) Targeting Notch in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-8859-4_8

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