Document Type : Original Article(s)
Authors
- Seyedeh Hananeh Ghafelehbashi 1
- Dina Sadeghizadeh 2
- Fatemeh Rohollah 2
- Saghar Pahlavanneshan 3
- Majid Sadeghizadeh 1
1 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
2 Department of Cellular and Molecular Sciences, Faculty of Advanced Sciences and Technology, Tehran University of Medical Sciences, Islamic Azad university, Tehran, Iran
3 Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Comprehensive Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract
Background: Acute myeloid leukemia (AML) is a complex disease characterized by clonal expansion of undifferentiated myeloid precursors, resulting in impaired hematopoiesis and bone marrow failure. Different genetic and environmental factors are believed to be involved in the pathogenesis of AML. Notch signaling with a tumor suppressing plays a role in myeloproliferative disorder and is a negative regulator of myeloid progenitor commitment. Crosstalk between Notch signaling and CXCR4 axis is a matter of debate in AML.
Method: In the current case-control study, we evaluated the expression level of CXCR4, JAG1, and MIB1, which are all involved or related to Notch signaling in adult AML patients. Blood samples were obtained from 25 AML and 17 healthy individuals and the expression level of the selected genes was evaluated via the real-time polymerase chain reaction.
Results: Our results revealed the increased expression of JAG1, but decreased expression of CXCR4 in AML patients in Iranian population of AML patients. Moreover, some gender-associated effects on the expression of JAG1 and CXCR4 were detected, which may be related to sex hormones. The expression level of MIB1 did not change significantly. The correlation analysis showed no correlations between the age of the patients and the expression levels of the genes.
Conclusion: Herein, for the first time, we suggested some new evidence regarding the complex role of Notch signaling-related genes (CXCR4 and JAG1) in the pathogenesis of AML in Iranian patients.
Keywords
How to cite this article:
Ghafelehbashi SH, Sadeghizadeh D, Rohollah F, Pahlavanneshan S, Sadeghizadeh M. Evaluation of the expression levels of Notch signaling pathway-related genes; JAG1, CXCR4, and MIB1 in acute myeloid leukemia patients. Middle East J Cancer. 2022;13(4):573-80. doi: 10.30476/mejc.2021.89042. 1504.
2.Takam Kamga P, Dal Collo G, Resci F, Bazzoni R, Mercuri A, Quaglia FM, et al. Notch signaling molecules as prognostic biomarkers for acute myeloid leukemia. Cancers (Basel). 2019;11(12):1958. doi: 10.3390/cancers11121958.
3.Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172-83. doi: 10.1038/nrc1567.
4.Zolghadr F, Sadeghizadeh M, Amirizadeh N, Hosseinkhani S, Nazem S. How benzene and its metabolites affect human marrow derived mesenchymal stem cells. Toxicol Lett. 2012;214(2):145-53. doi: 10.1016/j.toxlet.2012.08.015.
5.Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. 2010;19(5):698-711. doi: 10.1016/j.devcel.2010.10. 005.
6.Potter N, Miraki-Moud F, Ermini L, Titley I, Vijayaraghavan G, Papaemmanuil E, et al. Single cell analysis of clonal architecture in acute myeloid leukaemia. Leukemia. 2019;33(5):1113-23. doi: 10.1038/s41375-018-0319-2.
7.van Galen P, Hovestadt V, Wadsworth Ii MH, Hughes TK, Griffin GK, Battaglia S, et al. Single-cell RNA-Seq reveals AML hierarchies relevant to disease progression and immunity. Cell. 2019;176(6):1265-81.e24. doi: 10.1016/j.cell.2019.01.031.
8.Arindrarto W, Borrás DM, de Groen RAL, van den Berg RR, Locher IJ, van Diessen SAME, et al. Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing. Leukemia. 2021;35(1):47-61. doi: 10.1038/s41375-020-0762-8.
9.Suresh S, Irvine AE. The NOTCH signaling pathway in normal and malignant blood cell production. J Cell Commun Signal. 2015;9(1):5-13. doi: 10.1007/s12079-015-0271-0.
10.Grieselhuber NR, Klco JM, Verdoni AM, Lamprecht T, Sarkaria SM, Wartman LD, et al. Notch signaling in acute promyelocytic leukemia. Leukemia. 2013;27(7):1548-57. doi: 10.1038/leu.2013.68.
11.Tosello V, Ferrando AA. The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. Ther Adv Hematol. 2013;4(3):199-210. doi: 10.1177/2040620712471368.
12.Tsaouli G, Ferretti E, Bellavia D, Vacca A, Felli MP. Notch/CXCR4 partnership in acute lymphoblastic leukemia progression. J Immunol Res. 2019;2019: 5601396. doi: 10.1155/2019/5601396.
13.Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med. 2013;210(2):301-19. doi: 10.1084/ jem.20121484.
14.Murata-Ohsawa M, Tohda S, Nara N. Cellular analysis of growth suppression induced by the Notch ligands, Delta-1 and Jagged-1 in two myeloid leukemia cell lines. Int J Mol Med. 2004;14(2):223-6.
15.Burns CE, Traver D, Mayhall E, Shepard JL, Zon LI. Hematopoietic stem cell fate is established by the Notch-Runx pathway. Genes Dev. 2005;19(19):2331-42. doi: 10.1101/gad.1337005.
16.Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16(2):232-6. doi: 10.1038/nm.2080.
17.Katoh M, Katoh M. Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med. 2006;17(4):681-5.
18.Luxán G, Casanova JC, Martínez-Poveda B, Prados B, D’Amato G, MacGrogan D, et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular non-compaction cardiomyopathy. Nat Med. 2013;19(2): 193-201.
19.Kim SY, Lee CH, Midura BV, Yeung C, Mendoza A, Hong SH, et al. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis. 2008; 25(3):201-11. doi: 10.1007/s10585-007-9133-3.
20.Devine H, Tierney DK, Schmit-Pokorny K, McDermott K. Mobilization of hematopoietic stem cells for use in autologous transplantation. Clin J Oncol Nurs. 2010;14(2):212-22. doi: 10.1188/10.CJON.212-222.
21.Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res. 2004;64(8):2817-24. doi: 10.1158/0008-5472.can-03-3693.
22.Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770-6. doi: 10.1126/science.284.5415.770.
23.Williams CK, Segarra M, Sierra Mde L, Sainson RC, Tosato G, Harris AL. Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells. Cancer Res. 2008;68(6):1889-95. doi: 10.1158/0008-5472.CAN-07-2181.
24.Ye Q, Jiang J, Zhan G, Yan W, Huang L, Hu Y, et al. Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia. Sci Rep. 2016;6:26510. doi: 10.1038/srep26510.
25.Fathi AT, Grant S, Karp JE. Exploiting cellular pathways to develop new treatment strategies for AML. Cancer Treat Rev. 2010;36(2):142-50. doi: 10.1016/j.ctrv.2009.12.004.
26.Shafer D, Grant S. Update on rational targeted therapy in AML. Blood Rev. 2016;30(4):275-83. doi: 10.1016/j.blre.2016.02.001.
27.Kovall RA, Hendrickson WA. Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA. EMBO J. 2004;23(17):3441-51. doi: 10.1038/sj.emboj.7600349.
28.Kannan S, Sutphin RM, Hall MG, Golfman LS, Fang W, Nolo RM, et al. Notch activation inhibits AML growth and survival: a potential therapeutic approach. J Exp Med. 2013;210(2):321-37. doi: 10.1084/jem.20121527.
29.Li D, Masiero M, Banham AH, Harris AL. The NOTCH ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol. 2014;4:254. doi: 10.3389/fonc. 2014.00254.
30.Czemerska M, Pluta A, Szmigielska-Kaplon A, Wawrzyniak E, Cebula-Obrzut B, Medra A, et al. Jagged-1: a new promising factor associated with favorable prognosis in patients with acute myeloid leukemia. Leuk Lymphoma. 2015;56(2):401-6. doi: 10.3109/10428194.2014.917638.
31.Pelullo M, Quaranta R, Talora C, Checquolo S, Cialfi S, Felli MP, et al. Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL. Neoplasia. 2014;16(12):1007-17. doi: 10.1016/j.neo.2014.10.004.
32.Stirewalt DL, Meshinchi S, Kopecky KJ, Fan W, Pogosova-Agadjanyan EL, Engel JH, et al. Identification of genes with abnormal expression changes in acute myeloid leukemia. Genes Chromosomes Cancer. 2008;47(1):8-20. doi: 10.1002/ gcc.20500.
33.Selcuklu SD, Donoghue MT, Kerin MJ, Spillane C. Regulatory interplay between miR-21, JAG1 and 17beta-estradiol (E2) in breast cancer cells. Biochem Biophys Res Commun. 2012;423(2):234-9. doi: 10.1016/j.bbrc.2012.05.074.
34.Hong Z, Wei Z, Xie T, Fu L, Sun J, Zhou F, et al. Targeting chemokines for acute lymphoblastic leukemia therapy. J Hematol Oncol. 2021;14(1):48. doi: 10.1186/s13045-021-01060-y.
35.Monaco G, Belmont JW, Konopleva M, Andreeff M, Tavor S, Petit I, et al. Correlation between CXCR4 and homing or engraftment of acute myelogenous leukemia. Cancer Res. 2004;64(18):6832 author reply 6832-3. doi: 10.1158/0008-5472.CAN-04-1936.
36.Hu X, Mei S, Meng W, Xue S, Jiang L, Yang Y, et al. CXCR4-mediated signaling regulates autophagy and influences acute myeloid leukemia cell survival and drug resistance. Cancer Lett. 2018;425:1-12. doi: 10.1016/j.canlet.2018.03.024.
37.Peled A, Tavor S. Role of CXCR4 in the pathogenesis of acute myeloid leukemia. Theranostics. 2013;3(1):34-9. doi: 10.7150/thno.5150.
38.Staber PB, Linkesch W, Zauner D, Beham-Schmid C, Guelly C, Schauer S, et al. Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia. Oncogene. 2004;23(4):894-904. doi: 10.1038/sj.onc.1207192.