Kronik Lenfositik Lösemi Hastalarında Notch Ekspresyon Seviyeleri: Akan Hücre Ölçer ile Değerlendirilmesi
Abstract
Amaç: CD5+CD19+ malign B hücrelerin kemik iliği ve kanda birikmesi ile karakterize kronik lenfositik lösemi (KLL), Amerika ve Avrupa’da yetişkinlerde en sık gözlenen lösemi tipidir. CD38, ZAP70 ekspresyonları, immünoglobülin ağır zincir değişken bölge (IgVH) mutasyonları hastalığın klinik seyri hakkında bilgi sağlasa da KLL patogenezi henüz net olarak tanımlanmamıştır. Transmembran proteini olan Notch reseptörleri hücre çoğalması, farklılaşması ve apoptozis süreçlerinde immün homeostazın sağlanmasında oldukça önemlidir. Güncel çalışmalar, Notch moleküllerinin kanser gelişiminde rolü olduğunu göstemektedir. Bu çalışmada KLL tanısı almış hastalarda Notch seviyeleri analiz edilerek KLL patogenezindeki rolleri incelenmiştir.
Yöntem: KLL tanılı 15 hasta ve 9 sağlıklı bireyin periferik kanından izole edilen periferik kan mononükleer hücrelerde akan hücre ölçer ile Notch1, Notch2, Notch3 ve Notch4 seviyeleri değerlendirildi.
Bulgular: KLL hastalarında lenfosit, CD19+ B ve CD3+ T hücrelerde Notch1 ifadesinin arttığı, buna karşın Notch4 ifadesinin ise azaldığı gözlendi. Hasta ve sağlıklı bireyler arasında Notch2 ve Notch3 ifadeleri arasında anlamlı fark gözlenmedi.
Sonuç: Notch1hücreleri apoptoza karşı dirençli hale getirerek hücre sağ kalımı üzerine pozitif etkide bulunmaktadır. KLL hastalarında Notch1 gen ifadesinin yükseldiği ve kötü prognoz ile ilişkili olduğu bildirilmektedir. Bulgularımız akan hücre ölçer ile Notch ifadelerinin hastalarda hızlı bir şekilde değerlendirilebileceğini ve değişen Notch1 ve Notch4 ifadelerinin KLL patogenezinde incelenmesi gereken potansiyel belirteçler olarak öne çıkabileceğini göstermektedir.
Keywords
Ethical Statement
Bu çalışma İ.Ü. İTF Etik Kurulu tarafından 13.11.2017 tarih no:1301 ile etik onay almıştır.
Supporting Institution
Bu çalışma İstanbul Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi (Proje No: TDP-2019-32394) tarafından desteklenmiştir.
Project Number
TDP-2019-32394
Thanks
Bu çalışmaya verdiği katkı için rahmetli Prof. Dr. Melih AKTAN’a teşekkür ederiz.
References
- Kikushige Y. Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies. J Clin Exp Hematop. Dec 15 2020;60(4):146-158. doi:10.3960/jslrt.20036
- Braish J, Cerchione C, Ferrajoli A. An overview of prognostic markers in patients with CLL. Front Oncol. 2024;14:1371057. doi:10.3389/fonc.2024.1371057
- Koehrer S, Burger JA. Chronic Lymphocytic Leukemia: Disease Biology. Acta Haematol. 2024;147(1):8-21. doi:10.1159/000533610
- Brown JR. Clinical Risks for Chronic Lymphocytic Leukemia. J Natl Compr Canc Netw. Apr 2024;22(3)doi:10.6004/jnccn.2024.7020
- Sachan N, Sharma V, Mutsuddi M, Mukherjee A. Notch signalling: multifaceted role in development and disease. FEBS J. Jul 2024;291(14):3030-3059. doi:10.1111/febs.16815
- Cai J, Qiao Y, Chen L, Lu Y, Zheng D. Regulation of the Notch signaling pathway by natural products for cancer therapy. J Nutr Biochem. Jan 2024;123:109483. doi:10.1016/j.jnutbio.2023.109483
- Shi Q, Xue C, Zeng Y, et al. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther. May 27 2024;9(1):128. doi:10.1038/s41392-024-01828-x
- Feng M, Santhanam RK, Xing H, Zhou M, Jia H. Inhibition of gamma-secretase/Notch pathway as a potential therapy for reversing cancer drug resistance. Biochem Pharmacol. Feb 2024;220:115991. doi:10.1016/j.bcp.2023.115991
- Gragnani L, Lorini S, Marri S, Zignego AL. Role of Notch Receptors in Hematologic Malignancies. Cells. Dec 24 2020;10(1)doi:10.3390/cells10010016
- Meurette O, Mehlen P. Notch Signaling in the Tumor Microenvironment. Cancer Cell. Oct 8 2018;34(4):536-548. doi:10.1016/j.ccell.2018.07.009
- Saito T, Chiba S, Ichikawa M, et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity. May 2003;18(5):675-85. doi:10.1016/s1074-7613(03)00111-0
- Alderuccio JP, Lossos IS. NOTCH signaling in the pathogenesis of splenic marginal zone lymphoma-opportunities for therapy. Leuk Lymphoma. Feb 2022;63(2):279-290. doi:10.1080/10428194.2021.1984452
- Rosati E, Sabatini R, Rampino G, et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. Jan 22 2009;113(4):856-65. doi:10.1182/blood-2008-02-139725
- Harb H, Benamar M, Lai PS, et al. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections. Immunity. Jun 8 2021;54(6):1186-1199 e7. doi:10.1016/j.immuni.2021.04.002
- Benamar M, Chen Q, Chou J, et al. The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children. J Clin Invest. Jan 3 2023;133(1)doi:10.1172/JCI163235
- Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. Dec 1 2021;96(12):1679-1705. doi:10.1002/ajh.26367
- Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematology Am Soc Hematol Educ Program. 2009:353-61. doi:10.1182/asheducation-2009.1.353
- Kontomanolis EN, Kalagasidou S, Pouliliou S, et al. The Notch Pathway in Breast Cancer Progression. ScientificWorldJournal. 2018;2018:2415489. doi:10.1155/2018/2415489
- Sun J, Dong M, Xiang X, Zhang S, Wen D. Notch signaling and targeted therapy in non-small cell lung cancer. Cancer Lett. Mar 31 2024;585:216647. doi:10.1016/j.canlet.2024.216647
- Larose H, Prokoph N, Matthews JD, et al. Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target. Haematologica. Jun 1 2021;106(6):1693-1704. doi:10.3324/haematol.2019.238766
- Isık S, Gunden G, Davutoglu NO, et al. Kronik Lenfositik Lösemi Olgularında NOTCH1 Gen Amplifikasyonu. Osmangazi Journal of Medicine. 2023;46(1):104-109. doi:10.20515/otd.1329205
- Zou Y, Fan L, Xia Y, et al. NOTCH1 mutation and its prognostic significance in Chinese chronic lymphocytic leukemia: a retrospective study of 317 cases. Cancer Med. May 2018;7(5):1689-1696. doi:10.1002/cam4.1396
- Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. Jan 12 2012;119(2):521-9. doi:10.1182/blood-2011-09-379966
- Lopez-Lopez S, Romero de Avila MJ, Hernandez de Leon NC, et al. NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-gamma and TLR4 Signaling. Front Immunol. 2021;12:734966. doi:10.3389/fimmu.2021.734966
- Nwabo Kamdje AH, Mosna F, Bifari F, et al. Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood. Jul 14 2011;118(2):380-9. doi:10.1182/blood-2010-12-326694
- Rivas JR, Liu Y, Alhakeem SS, et al. Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia. Leukemia. Nov 2021;35(11):3188-3200. doi:10.1038/s41375-021-01217-1
- Ozden O, Gelmez MY, Çınar S, Deniz G, Aktan M. Intracellular Levels of IL-10 and STAT3 in Patients with Chronic Lymphocytic Leukemia. Clinical and Experimental Health Sciences. 2023;13(1):99-104. doi:10.33808/clinexphealthsci.1056727
- Lopez-Guerra M, Xargay-Torrent S, Fuentes P, et al. Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. Oncogene. Feb 2020;39(6):1185-1197. doi:10.1038/s41388-019-1053-6Cree BAC, Arnold DL, Chataway J, et al. Secondary progressive multiple sclerosis: new insights. Neurology. 2021;97(8):378-388. doi:10.1212/WNL.0000000000012323
Abstract
Objective: Chronic lymphocytic leukemia (CLL), characterized by the accumulation of CD5+CD19+ malignant B cells in the bone marrow and blood, is the most common type of leukemia in adults in Western countries. While CD38 and ZAP70 expression and immunoglobulin heavy chain variable region (IgVH) mutations provide insights into the clinical outcome of the disease, the pathogenesis of CLL has not yet been fully elucidated. Notch receptors, which are transmembrane proteins, play a critical role in regulating cell proliferation, differentiation, and apoptosis. Recent studies have demonstrated the involvement of Notch proteins in various types of cancer. It has been reported that 10% of CLL patients had Notch1 mutations, and this mutation is associated with poorer prognosis. In this study, the levels of Notch molecules were analyzed in CLL patients to investigate their roles in the pathogenesis of the disease.
Methods: Notch-1, Notch2, Notch3, and Notch4 levels were analyzed by flow cytometry in peripheral blood mononuclear cells isolated from heparinized blood samples of 15 CLL patients and 9 healthy individuals.
Results: Compared to healthy individuals, increased Notch1and decreased Notch4 levels were found in total lymphocytes, B cells, and T lymphocytes in CLL patients. No significant differences were detected in Notch2 and Notch3 expression between patients and healthy individuals.
Conclusion: Recent studies showed that Notch1enhances cell survival and increases resistance to apoptosis. Additionally, increased Notch1mRNA expression has been reported in CLL patients, which may be associated with a poorer disease prognosis. This study, through flow cytometry analysis, demonstrated elevated Notch1protein levels, suggesting that Notch1could be a potential new biomarker involved in the pathogenesis of CLL.
Keywords
Project Number
TDP-2019-32394
References
- Kikushige Y. Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies. J Clin Exp Hematop. Dec 15 2020;60(4):146-158. doi:10.3960/jslrt.20036
- Braish J, Cerchione C, Ferrajoli A. An overview of prognostic markers in patients with CLL. Front Oncol. 2024;14:1371057. doi:10.3389/fonc.2024.1371057
- Koehrer S, Burger JA. Chronic Lymphocytic Leukemia: Disease Biology. Acta Haematol. 2024;147(1):8-21. doi:10.1159/000533610
- Brown JR. Clinical Risks for Chronic Lymphocytic Leukemia. J Natl Compr Canc Netw. Apr 2024;22(3)doi:10.6004/jnccn.2024.7020
- Sachan N, Sharma V, Mutsuddi M, Mukherjee A. Notch signalling: multifaceted role in development and disease. FEBS J. Jul 2024;291(14):3030-3059. doi:10.1111/febs.16815
- Cai J, Qiao Y, Chen L, Lu Y, Zheng D. Regulation of the Notch signaling pathway by natural products for cancer therapy. J Nutr Biochem. Jan 2024;123:109483. doi:10.1016/j.jnutbio.2023.109483
- Shi Q, Xue C, Zeng Y, et al. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther. May 27 2024;9(1):128. doi:10.1038/s41392-024-01828-x
- Feng M, Santhanam RK, Xing H, Zhou M, Jia H. Inhibition of gamma-secretase/Notch pathway as a potential therapy for reversing cancer drug resistance. Biochem Pharmacol. Feb 2024;220:115991. doi:10.1016/j.bcp.2023.115991
- Gragnani L, Lorini S, Marri S, Zignego AL. Role of Notch Receptors in Hematologic Malignancies. Cells. Dec 24 2020;10(1)doi:10.3390/cells10010016
- Meurette O, Mehlen P. Notch Signaling in the Tumor Microenvironment. Cancer Cell. Oct 8 2018;34(4):536-548. doi:10.1016/j.ccell.2018.07.009
- Saito T, Chiba S, Ichikawa M, et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity. May 2003;18(5):675-85. doi:10.1016/s1074-7613(03)00111-0
- Alderuccio JP, Lossos IS. NOTCH signaling in the pathogenesis of splenic marginal zone lymphoma-opportunities for therapy. Leuk Lymphoma. Feb 2022;63(2):279-290. doi:10.1080/10428194.2021.1984452
- Rosati E, Sabatini R, Rampino G, et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. Jan 22 2009;113(4):856-65. doi:10.1182/blood-2008-02-139725
- Harb H, Benamar M, Lai PS, et al. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections. Immunity. Jun 8 2021;54(6):1186-1199 e7. doi:10.1016/j.immuni.2021.04.002
- Benamar M, Chen Q, Chou J, et al. The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children. J Clin Invest. Jan 3 2023;133(1)doi:10.1172/JCI163235
- Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. Dec 1 2021;96(12):1679-1705. doi:10.1002/ajh.26367
- Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematology Am Soc Hematol Educ Program. 2009:353-61. doi:10.1182/asheducation-2009.1.353
- Kontomanolis EN, Kalagasidou S, Pouliliou S, et al. The Notch Pathway in Breast Cancer Progression. ScientificWorldJournal. 2018;2018:2415489. doi:10.1155/2018/2415489
- Sun J, Dong M, Xiang X, Zhang S, Wen D. Notch signaling and targeted therapy in non-small cell lung cancer. Cancer Lett. Mar 31 2024;585:216647. doi:10.1016/j.canlet.2024.216647
- Larose H, Prokoph N, Matthews JD, et al. Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target. Haematologica. Jun 1 2021;106(6):1693-1704. doi:10.3324/haematol.2019.238766
- Isık S, Gunden G, Davutoglu NO, et al. Kronik Lenfositik Lösemi Olgularında NOTCH1 Gen Amplifikasyonu. Osmangazi Journal of Medicine. 2023;46(1):104-109. doi:10.20515/otd.1329205
- Zou Y, Fan L, Xia Y, et al. NOTCH1 mutation and its prognostic significance in Chinese chronic lymphocytic leukemia: a retrospective study of 317 cases. Cancer Med. May 2018;7(5):1689-1696. doi:10.1002/cam4.1396
- Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. Jan 12 2012;119(2):521-9. doi:10.1182/blood-2011-09-379966
- Lopez-Lopez S, Romero de Avila MJ, Hernandez de Leon NC, et al. NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-gamma and TLR4 Signaling. Front Immunol. 2021;12:734966. doi:10.3389/fimmu.2021.734966
- Nwabo Kamdje AH, Mosna F, Bifari F, et al. Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood. Jul 14 2011;118(2):380-9. doi:10.1182/blood-2010-12-326694
- Rivas JR, Liu Y, Alhakeem SS, et al. Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia. Leukemia. Nov 2021;35(11):3188-3200. doi:10.1038/s41375-021-01217-1
- Ozden O, Gelmez MY, Çınar S, Deniz G, Aktan M. Intracellular Levels of IL-10 and STAT3 in Patients with Chronic Lymphocytic Leukemia. Clinical and Experimental Health Sciences. 2023;13(1):99-104. doi:10.33808/clinexphealthsci.1056727
- Lopez-Guerra M, Xargay-Torrent S, Fuentes P, et al. Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. Oncogene. Feb 2020;39(6):1185-1197. doi:10.1038/s41388-019-1053-6Cree BAC, Arnold DL, Chataway J, et al. Secondary progressive multiple sclerosis: new insights. Neurology. 2021;97(8):378-388. doi:10.1212/WNL.0000000000012323
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Immunology (Other), Haematology |
| Journal Section | Research Articles |
| Authors | |
| Project Number | TDP-2019-32394 |
| Publication Date | June 30, 2025 |
| Submission Date | December 9, 2024 |
| Acceptance Date | March 26, 2025 |
| Published in Issue | Year 2025 Volume: 8 Issue: 2 |
The articles in the Journal of "Acta Medica Nicomedia" are open access articles licensed under a Creative Commons Attribution-ShareAlike 4.0 International License at the web address https://dergipark.org.tr/tr/pub/actamednicomedia