Notch 1 and NF-κB Expression and Clinical Correlation in Chinese Patients with Lymphoblastic Lymphoma


T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) is commonly associated with Notch 1 mutations. There is limited data on the relationship between Notch l and NF-κB expression and clinical features in LBL. We evaluated the expression of Notch l and NF-κB in LBL using immunohistochemistry and analyzed their relationship with clinical characteristics, treatment results, and survival. From October 2000 to August 2008, 34 untreated patients with LBL were enrolled in the study. Median age was 11.8 years (range, 1 - 25 years). Twenty-five patients were diagnosed with T-LBL and 9 patients with B-LBL. Most patients received chemotherapy consisting of modified ALL-BFM- 90. Notch l showed high expression in 68% of T-LBL and low expression in 100% of B-LBL (p = 0.015). High expression of Notch l positively correlated with presence of a mediastinal mass but not with 5-year event free survival (EFS) in T-LBL. NF-κB showed high expression in 65% of all patients with LBL, with no difference between T- and B-LBL. NF-κB expression was higher in T-LBL patients with bulky disease and B symptom; it did not correlate with 5-year EFS in T-LBL. Expression of Notch 1 and NF-κB strongly correlated (p = 0.014) in T-LBL. Notch 1 is highly ex- pressed in T-LBL. NF-κB is highly expressed in all patients with LBL with no difference between T-LBL and B-LBL. Notch 1 expression was significantly associated with NF-κB expression in T-LBL. Notch l and NF-κB may play an important role in the development of T-LBL; further investigation is warranted.

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L. Lin, X. Sun, J. Wang, Z. Zhen, S. Lin, G. Tong and Y. Chen, "Notch 1 and NF-κB Expression and Clinical Correlation in Chinese Patients with Lymphoblastic Lymphoma," Journal of Cancer Therapy, Vol. 4 No. 3A, 2013, pp. 441-447. doi: 10.4236/jct.2013.43A053.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] H. S. Steven, C. Elias, L. H. Nancy, et al., “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues,” IARC, France, 2008.
[2] A. Reiter, M. Schrappe, W. D. Ludwig, et al., “Intensive ALL-Type Therapy without Local Radiotherapy Provides a 90% Event-Free Survival for Children with T-Cell Lymphoblastic Lymphoma: A BFM Group Report,” Blood, Vol. 95, No. 2, 2000, pp. 416-421.
[3] B. Burkhardt, W. Woessmann, M. Zimmermann, et al., “Impact of Cranial Radiotherapy on Central Nervous System Prophylaxis in Children and Adolescents with Central Nervous System-Negative Stage III or IV Lymphoblastic Lymphoma,” Journal of Clinical Oncology, Vol. 24, No. 3, 2006, pp. 491-499. doi:10.1200/JCO.2005.02.2707
[4] L. W. Ellisen, J. Bird, D. C. West, et al., “TAN21, the Human Homolog of the Drosophila Notch Gene, Is Broken by Chromosomal Translocations in T Lymphoblastic Neoplasms,” Cell, Vol. 66, No. 4, 1991, pp. 649-661. doi:10.1016/0092-8674(91)90111-B
[5] S. Artavanis-Tsakonas, K. Matsuno and M. E. Fortini, “Notch Signaling,” Science, Vol. 268, Vol. 5208, 1995, pp. 225-232.
[6] U. Koch and F. Radtke, “Notch and Cancer: A DoubleEdged Sword,” Cellular and Molecular Life Sciences, Vol. 64, No. 21, 2007, pp. 2746-2762. doi:10.1007/s00018-007-7164-1
[7] A. P. Weng, A. A. Ferrando, W. Lee, et al., “Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia,” Science, Vol. 306, No. 5694, 2004, pp. 269-271. doi:10.1126/science.1102160
[8] V. Asnafi, A. Buzyn, S. Le Noir, et al., “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, Vol. 113, No. 17, 2009, pp. 3918-3924. doi:10.1182/blood-2008-10-184069
[9] S. Breit, M. Stanulla, T. Flohr, et al., “Activating NOTCH1 Mutations Predict Favorable Early Treatment Response and Long-Term Outcome in Childhood Precursor T-Cell Lymphoblastic Leukemia,” Blood, Vol. 108, No. 4, 2006, pp.1151-1157. doi:10.1182/blood-2005-12-4956
[10] A. Larson Gedman, Q. Chen, S. Kugel Desmoulin, et al., “The Impact of NOTCH1, FBW7 and PTEN Mutations on Prognosis and Downstream Signaling in Pediatric TCell Acute Lymphoblastic Leukemia: A Report from the Children’s Oncology Group,” Leukemia, Vol. 23, No. 8, 2009, pp. 1417-1425. doi:10.1038/leu.2009.64
[11] T. Palomero, K. C. Barnes, P. J. Real, et al., “CUTLL1, a Novel Human T-Cell Lymphoma Cell Line with t(7;9) Rearrangement, Aberrant NOTCH1 Activation and High Sensitivity to Gamma-Secretase Inhibitors,” Leukemia, Vol. 20, No. 7, 2006, pp. 1279-1287. doi:10.1038/sj.leu.2404258
[12] W. S. Pear, J. C. Aster, M. L. Scott, et al., “Exclusive Development of T Cell Neoplasms in Mice Transplanted with Bone Marrow Expressing Activated Notch Alleles,” The Journal of Experimental Medicine, Vol. 183, No. 5, 1996, pp. 2283-2291. doi:10.1084/jem.183.5.2283
[13] D. Paris, A. Quadros and N. Patel, “Inhibition of Angiogenesis and Tumor Growth by Beta and Gamma-Secretase Inhibitors,” European Journal of Pharmacology, Vol. 514, No. 1, 2005, pp. 1-15. doi:10.1016/j.ejphar.2005.02.050
[14] M. L. Bernal, C. M. Lovly and L. Ratner, “The Role of NF-{Kappa} B-1 and NF-{kappa} B-2-Mediated Resistance to Apoptosis in Lymphomas,” Proceedings of the National Academy of Sciences, Vol. 103 No. 24, 2006, pp. 9220-9222. doi:10.1073/pnas.0507809103
[15] T. ilimas, J. Mascarenhas and T. Palomero, “Targeting the NF-kB Signaling Pathway in Notch1-Induced T-Cell Leukemia,” Nature Medicine, Vol. 13, No. 1, 2007, pp. 70-77. doi:10.1038/nm1524
[16] M. L. Carcangiu, J. T. Chambers and I. M. Voynick, “Immunohistochemical Evaluation of Estrogen and Progesterone Receptor Content in 183 Patients with Endometrial Carcinoma. Part I: Clinical and Histologic Correlations,” American Journal of Clinical Pathology, Vol. 94, No. 3, 1990, pp. 247-254.
[17] X. Y. Li, F. Gounari, A. Protopopov, et al., “Oncogenesis of T-ALL and Nonmalignant Consequences of Overexpressing Intracellular NOTCH1,” Journal of Experimental Medicine, Vol. 205, No. 12, 2008, pp. 2851-2861. doi:10.1084/jem.20081561
[18] J. Franziska, A. Ioannis, F. Reinhold, et al., “Activated Notch1 Signaling Promotes Tumor Cell Proliferation and Survival in Hodgkin and Anaplastic Large Cell Lymphoma,” Blood, Vol. 99, No. 9, 2002, pp. 3398-3403. doi:10.1182/blood.V99.9.3398
[19] M. R. Kamstrup, L. M. Gjerdrum, E. Biskup, et al., “Notch1 as a Potential Therapeutic Target in Cutaneous T-Cell Lymphoma,” Blood, Vol. 116, No. 14, 2010, pp. 2504-2512. doi:10.1182/blood-2009-12-260216
[20] Y.-M. Zhu, W.-L. Zhao and J.-F. Fu, “NOTCH1 Mutations in T-Cell Acute Lymphoblastic Leukemia: Prognostic Significance and Implication in Multifactorial Leukemogenesis,” Clinical Cancer Research, Vol. 15, No.12, 2006, pp. 3043-3049.
[21] M. R. Mansour, M. L. Sulis, V. Duke, et al., “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, Vol. 27, No. 26, 2009, pp. 4352-4356. doi:10.1200/JCO.2009.22.0996
[22] M. van Grotel, J. P. Meijerink, E. R. van Wering, et al., “Prognostic Significance of Molecular-Cytogenetic Abnormalities in Pediatric T-ALL Is Not Explained by Immunophenotypic Differences,” Leukemia, Vol. 22, No. 1, 2008, pp. 124-131. doi:10.1038/sj.leu.2404957
[23] C. Callens, F. Baleydier, E. Lengline, et al., “Clinical Impact of NOTCH1 and/or FBXW7 Mutations, FLASH Deletion, and TCR Status in Pediatric T-Cell Lymphoblastic Lymphoma,” Journal of Clinical Oncology, Vol. 30, No. 16, 2012, pp. 1966-1973. doi:10.1200/JCO.2011.39.7661
[24] D. Bellavia, A. F. Campese, E. Alesse, et al., “Constitutive Activation of NF-kappaB and T-Cell Leukemia/Lymphoma in Notch3 Transgenic Mice,” The EMBO Journal, Vol. 19, No. 13, 2000, pp. 3337-3348. doi:10.1093/emboj/19.13.3337
[25] T. Vilimas, J. Mascarenhas, T. Palomero, et al., “Targeting the NF-kappaB Signaling Pathway in Notch1-Induced T-Cell Leukemia,” Nature Medicine, Vol. 13, No. 1, 2007, pp. 70-77. doi:10.1038/nm1524
[26] I. Aifantis, T. Vilimas and S. Buonamici, “Notches, NF Kappa Bs and the Making of T Cell Leukemia,” Cell Cycle, Vol. 6, No. 4, 2007, pp. 403-406. doi:10.4161/cc.6.4.3858
[27] P. Bavi, S. Uddin, R. Bu, et al., “The Biological and Clinical Impact of Inhibition of NF-κB-Initiated Apoptosis in Diffuse Large B Cell Lymphoma (DLBCL),” The Journal of Pathology, Vol. 224, No. 3, 2011, pp. 355-366. doi:10.1002/path.2864
[28] L. Z. Jiang, P. Wang, B. Deng, et al., “Overexpression of Forkhead Box M1 Transcription Factor and Nuclear Factor-κB in Laryngeal Squamous Cell Carcinoma: A Potential Indicator for Poor Prognosis,” Human Pathology, Vol 42, No. 8, 2011, pp. 1185-1193. doi:10.1016/j.humpath.2010.06.017

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