Volume 27, Issue 6 (11-2023)                   IBJ 2023, 27(6): 357-365 | Back to browse issues page

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Sharma V, Namdeo M, Kumar P, Kumar Mitra D, Chattopadhyay P, Sazawal S, et al . Increased Expression of NOTCH-1 and T Helper Cell Transcription Factors in Patients with Acquired Aplastic Anemia. IBJ 2023; 27 (6) :357-365
URL: http://ibj.pasteur.ac.ir/article-1-3754-en.html
Background: Acquired aplastic anemia (aAA) is an autoimmune disease in which auto-aggressive T cells destroy hematopoietic progenitors. T-cell differentiation is controlled by transcription factors that interact with NOTCH-1, which influences the respective T-cell lineages. Notch signaling also regulates the bone marrow (BM) microenvironment. The present study aimed to assess the gene expressions of NOTCH-1 and T helper cell transcription factors in the acquired aplastic anemia patients.  
Methods: Using quantitative real-time PCR, we studied the mRNA expression level for NOTCH-1, its ligands (DLL-1 and JAG-1), and T helper cell transcription factors (T-BET, GATA-3, and ROR-γt) in both peripheral blood and BM of aAA patients and healthy controls. Further, patients of aplastic anemia were stratified by their disease severity as per the standard criteria.
Results: The mRNA expression level of NOTCH-1, T-BET, GATA-3, and ROR-γT genes increased in aAA patients compared to healthy controls. There was no significant difference in the mRNA expression of Notch ligands between patients and controls. The mRNA expression level of the above-mentioned genes was found to be higher in severe aplastic anemia and very severe aplastic anemia than non-severe aplastic anemia patients. In addition, NOTCH-1 and T helper cell-specific transcription factors enhanced in aAA. We also observed a significant correlation between the genes and hematological parameters in patients.
Conclusion: The interaction between NOTCH-1, T-BET, GATA-3, and
ROR-γT might lead to the activation, proliferation, and polarization of T helper cells and subsequent BM destruction. The mRNA expression levels of genes varied with disease severity, which may contribute to pathogenesis of aAA.
Type of Study: Full Length/Original Article | Subject: Cancer Biology

1. Sharma V, Kumar P, Kumar R, Chakraborty S, Namdeo M, Sazawal S, Kanga U, Seth T, Dipendra Kumar M. Interferon-gamma and perforin-positive T cells in acquired aplastic anemia: implication in therapeutic response. Clinical and experimental immunology 2022; 207(3): 272-278. [DOI:10.1093/cei/uxab006]
2. Zeng Y, Katsanis E. The complex pathophysiology of acquired aplastic anaemia. Clinical and experimental immunology 2015; 180(3): 361-370. [DOI:10.1111/cei.12605]
3. Risitano AM. Immunosuppressive therapies in the management of immune-mediated marrow failures in adults: where we stand and where we are going. British journal of haematology 2011; 152(2): 127-140. [DOI:10.1111/j.1365-2141.2010.08439.x]
4. Rauen T, Grammatikos AP, Hedrich CM, Floege J, Tenbrock K, Ohl K, Kyttaris VC, Tsokos GC. cAMP-responsive element modulator alpha (CREMalpha) contributes to decreased Notch-1 expression in T cells from patients with active systemic lupus erythematosus (SLE). The journal of biological chemistry 2012; 287(51): 42525-4232. [DOI:10.1074/jbc.M112.425371]
5. Maekawa Y, Tsukumo S, Chiba S, Hirai H, Hayashi Y, Okada H, Kishihara K, Yasutomo K. Delta1-Notch3 Interactions Bias the Functional Differentiation of Activated CD4+ T Cells. Immunity 2003; 19(4):549-559. [DOI:10.1016/S1074-7613(03)00270-X]
6. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004; 117(4): 515-526. [DOI:10.1016/S0092-8674(04)00451-9]
7. Andersen P, Uosaki H, Shenje LT, Kwon C. Non-canonical Notch signaling: Emerging role and mechanism. Trends in Cell Biology 2012; 22(5): 257-565. [DOI:10.1016/j.tcb.2012.02.003]
8. Minter LM, Osborne BA. Canonical and non-canonical Notch signaling in CD4+ T cells. Current topics in microbiology and immunology 2012; 360: 99-114. [DOI:10.1007/82_2012_233]
9. Bellone M. Autoimmune Disease: Pathogenesis. Encyclopedia of Life Sciences 2005; reterieved from: https://onlinelibrary.wiley.com/doi/epdf/10.1038/npg.els.0004000. [DOI:10.1038/npg.els.0004000]
10. Palaga T, Minter LM. Notch signaling and its emerging role in autoimmunity. Frontiers in biology 2013; 8(3): 279-294. [DOI:10.1007/s11515-012-1209-z]
11. Jiao Z, Wang W, Guo M, Zhang T, Chen L, Wang Y, You H, Li J. Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis. Scandinavian journal of rheumatology 2010; 39(1): 26-32. [DOI:10.3109/03009740903124424]
12. Roderick JE, Gonzalez-Perez G, Kuksin CA, Dongre A, Roberts ER, Srinivasan J, Jr CA, Fauq AH, Golde TE, Miele L, Minter LM. Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. The journal of experimental medicine 2013; 210(7): 1311-1329. [DOI:10.1084/jem.20112615]
13. Deng S, Zeng Y, Wu L, Hu Z, Shen J, Shen Y, Shen Y, Zhou Y, Chen J, Lin S. The regulatory roles of VEGF-Notch signaling pathway on aplastic anemia with kidney deficiency and blood stasis. Journal of cellular biochemistry 2019; 120(2): 2078-2089 [DOI:10.1002/jcb.27516]
14. Li H, Wang L, Pang Y, Jiang Z, Liu Z, Xiao H, et al. In patients with chronic aplastic anemia, bone marrow-derived MSCs regulate the Treg/Th17 balance by influencing the Notch/RBP-J/FOXP3/RORγt pathway. Scientific reports 2017; 7: 42488. [DOI:10.1038/srep42488]
15. Mahapatra M, Singh PK, Agarwal M, Prabhu M, Mishra P, Seth T, et al. Epidemiology,clinico-haematological profile and management of aplastic Anaemia: AIIMS experience. The journal of the association of physicians of india 2015; 63(3 Suppl): 30-35.
16. Jain D, Raina V, Fauzdar A, Mishra M, Tyagi N, Mahajan A, Kalal IG, Dayakar S, Mishra P, Malik AA, Kumar A, Malik B K. Chromosomal breakage study in aplastic anemia patients in india. Asian journal of medical sciences 2013; 2: 227-232.
17. Adhikari S, Nayek K, Bandyopadhyay A, Mandal P. Implication of therapeutic outcomes associated with molecular characterization of paediatric aplastic anaemia. Biochemistry and biophysics reports 2021; 25: 100899. [DOI:10.1016/j.bbrep.2020.100899]
18. Singh I, Nunia V, Sharma R, Barupal J, Govindaraj P, Jain R, Gupta GN, GoyaPK . Mutational analysis of telomere complex genes in Indian population with acquired aplastic anemia. Leukemia research 2015; 7:S0145-S2126. [DOI:10.1016/j.leukres.2015.08.018]
19. Bruce M. Camitta, E. Donnall Thomas, David G. Nathan, Robert P. Gale, Kenneth J. Kopecky, Joel M. Rappeport, George Santos, E.C. Gordon-Smith, Rainer Storb. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood 1979; 53(3): 504-514. [DOI:10.1182/blood.V53.3.504.504]
20. Camitta BM, Storb R, Thomas ED. Aplastic anemia (first of two parts): pathogenesis, diagnosis, treatment, and prognosis. The New England journal of medicine 1982; 306(11): 645-652. [DOI:10.1056/NEJM198203183061105]
21. Marsh JCW, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, Keidan J, LaurieA, Martin A, Mercieca J, Killick SB, StewartR, Yin JA L. Guidelines for the diagnosis and management of aplastic anaemia. British journal of haematology 2009; 147(1): 43-70. [DOI:10.1111/j.1365-2141.2009.07842.x]
22. Niimi H, Pardali K, Vanlandewijck M, Heldin C-H, Moustakas A. Notch signaling is necessary for epithelial growth arrest by TGF-β. The journal of cell biology 2007; 176(5): 695-707. [DOI:10.1083/jcb.200612129]
23. Nakamori Y, Liu B, Ohishi K, Suzuki K, Ino K, Matsumoto T, MasuyaM, NishikawaH, ShikuH, HamadaH, KatayamaN. Human bone marrow stromal cells simultaneously support B and T/NK lineage development from human haematopoietic progenitors: a principal role for flt3 ligand in lymphopoiesis. British journal of haematology 2012; 157(6): 674-686. [DOI:10.1111/j.1365-2141.2012.09109.x]
24. Higashi T, Hashimoto K, Takagi R, Mizuno Y, Okazaki Y, Tanaka Y, MatsushitaS. Curdlan induces DC-Mediated Th17 polarization via jagged1 activation in humand endritic cells. Allergology international : official journal of the japanese society of allergology 2010; 59: 161-166. [DOI:10.2332/allergolint.09-OA-0103]
25. Du HZ, Wang Q, Ji J, Shen BM, Wei SC, Liu LJ, Ding J, Ma D, WangW, Peng J, Hou M. Expression of IL-27, Th1 and Th17 in patients with aplastic anemia. Journal of clinical immunology 2013; 33(2): 436-445. [DOI:10.1007/s10875-012-9810-0]
26. Shan N, Zhu X, Peng J, Qin P, Zhuang X, Wang H, Hou M. Interleukin 18 and interleukin 18 binding protein in patients with idiopathic thrombocytopenic purpura. British journal of haematology 2009; 144(5): 755-761. [DOI:10.1111/j.1365-2141.2008.07520.x]
27. Kong JS, Yoo SA, Kim HS, Kim HA, Yea K, Ryu S-H, Chung YJ, ChoCS, Kim WU. Inhibition of synovial hyperplasia, rheumatoid T cell activation, and experimental arthritis in mice by sulforaphane, a naturally occurring isothiocyanate. Arthritis and rheumatism 2010; 62(1): 159-170. [DOI:10.1002/art.25017]
28. Ngo ML, Mahdi F, Kolte D, Shariat-Madar Z. Upregulation of prolylcarboxypeptidase (PRCP) in lipopolysaccharide (LPS) treated endothelium promotes inflammation. Journal of inflammation 2009; 6(1): 3. [DOI:10.1186/1476-9255-6-3]
29. Song X, Zhang L, Zhang S, Wang A, Wu Y, Wang X, Liu B. Discorea nipponica saponins restore the Th17/Treg balance in aplastic anemia through the Notch/RBPJκ/FOXP3/RORγt axis. Journal of king saud university - science 2020; 32(2): 1664-1672. [DOI:10.1016/j.jksus.2019.12.026]
30. Minter LM, Turley DM, Das P, Shin HM, Joshi I, Lawlor RG, Cho OH, PalagaT, GottipatiS, Telfer JC, Kostura L, Fauq AH, SimpsonK, Such KA, MieleL, Golde TE, Miller SD, Osborne BA. Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nature immunology 2005; 6(7): 680-688. [DOI:10.1038/ni1209x]
31. Sodsai P, Hirankarn N, Avihingsanon Y, Palaga T. Defects in Notch1 upregulation upon activation of T cells from patients with systemic lupus erythematosus are related to lupus disease activity. Lupus 2008; 17(7): 645-653. [DOI:10.1177/0961203308089406]
32. Ma D, Dai J, Zhu X, Yan S, Zhao P, Zhang J, ZhuY, Sun J, Peng J, Ji C, Hou M. Aberrant expression of Notch signaling molecules in patients with immune thrombocytopenic purpura. Annals of hematology 2010; 89(2): 155-161. [DOI:10.1007/s00277-009-0790-y]
33. Sharma V, Rawat S, Gupta S, Tamta S, Sharma R, Seth T, Mohanty S. Human acquired aplastic anemia patients' bone-marrow-derived mesenchymal stem cells are not influenced by hematopoietic compartment and maintain stemness and immune properties. Anemia 2021; 2021: 6678067. [DOI:10.1155/2021/6678067]
34. Solomou EE, Keyvanfar K, Young NS. T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood 2006; 107(10): 3983-3991. [DOI:10.1182/blood-2005-10-4201]
35. Shan NN, Hu Y, Liu X, Wang X, Yuan D, Li Y. Imbalanced expression of T-bet and T cell immunoglobulin mucin-3 in patients with aplastic anaemia. Journal of clinical immunology 2013; 33(4): 809-8016. [DOI:10.1007/s10875-013-9864-7]
36. Chen H, Luo Z, Shen H, Ren C, Li Z, Tang J, Wang J, Wu T. Research on the roles of transcription factors T-bet and GATA-3 in aplastic anemia. Clinical laboratory 2014; 60(2): 291-295. [DOI:10.7754/Clin.Lab.2013.121004]
37. Wu X, Li Y, Zhu K, Wang Z, Chen S, Yang L. GATA-1, -2 and -3 genes expression in bone marrow microenviroment with chronic aplastic anemia. Hematology 2007; 12(4): 331-335. [DOI:10.1080/10245330701255288]
38. Zhang HX, Wu GS, Guo WL. Changes and significances of Th1/Th2, related cytokines and T cell subgroup in aplastic anemia patients. Journal of Hainan medical university 2016; 22(10): 96-98.
39. Lu T, Liu Y, Li P, Yu S, Huang X, Ma D, Ji C. Decreased circulating Th22 and Th17 cells in patients with aplastic anemia. Clinica chimica acta; international journal of clinical chemistry 2015; 450: 90-96. [DOI:10.1016/j.cca.2015.07.031]
40. Yu Z, Huang Z, Dai X, Wu X, Huang J. Th1/Th2 Imbalance in the Pathogenesis of Chronic Aplastic Anemia. Journal of hard tissue biology 2014; 23(4): 455-460. [DOI:10.2485/jhtb.23.455]
41. Shao Z, Jun W, Fu R, Li L, Liu H, Qu W, RuaE, Liang Y, Liu H, Wu Y, Wang G, Song J, Wang H, Xing L, Guan J, Wang X. Study on the dendritic cell subsets and their relationship with the expressions of T-Bet and GATA-3 in peripheral lymphocytes of severe aplastic anemia patients. Blood 2008; 112(11): 4901. [DOI:10.1182/blood.V112.11.4901.4901]
42. Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 2007; 27(1):100-110. [DOI:10.1016/j.immuni.2007.04.018]
43. Keerthivasan S, Suleiman R, Lawlor R, Roderick J, Bates T, Minter L, Anguita J, Juncadella I, Nickoloff BJ, Le Poole C, Miele L, Osborne BA. Notch signaling regulates mouse and human Th17 differentiation. The journal of immunology 2011; 187(2): 692-701. [DOI:10.4049/jimmunol.1003658]
44. Deftos ML, He YW, Ojala EW, Bevan MJ. Correlating notch signaling with thymocyte maturation. Immunity 1998; 9(6): 777-786. [DOI:10.1016/S1074-7613(00)80643-3]

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