Login Register Cart 0
Cross-Sectional Study

Evaluation of Expression Profile of Patients with Acute Myeloid Leukemia in Response to Azacitidine with Biological System Approach

Author(s): Rasta Hejab, Hamzeh Rahimi, Hamid Abedinlou and Pegah Ghoraeian*

Volume 12, Issue 3, 2023

Published on: 12 September, 2023

Page: [233 - 242] Pages: 10

DOI: 10.2174/2211536612666230825152826

Price: $65

Abstract

Background: Acute myeloid leukemia (AML) is a prevalent type of leukemia that is associated with high rates of chemoresistance, including resistance to Azacitidine (AZA). Understanding the molecular mechanisms of chemoresistance can lead to the development of novel therapeutic approaches. In this study, we aimed to identify dysregulated miRNAs and their target genes involved in chemoresistance to AZA in AML patients.

Methods: We analyzed expression profiles from two GEO datasets (GSE16625 and GSE77750) using the "Limma" package in R. We identified 29 differentially expressed miRNAs between AML patients treated with AZA and healthy individuals. MultiMiR package of R was used to predict target genes of identified miRNAs, and functional enrichment analysis was performed using FunRich software. Protein-protein interaction networks were constructed using STRING and visualized using Cytoscape. MiR-582 and miR- 597 were the most up- and down-regulated miRNAs, respectively. Functional enrichment analysis revealed that metal ion binding, regulation of translation, and proteoglycan syndecan-mediated signaling events were the most enriched pathways. The tumor necrosis factor (TNF) gene was identified as a hub gene in the protein-protein interaction network.

Discussion: Our study identified dysregulated miRNAs and their target genes in response to AZA treatment in AML patients. These findings provide insights into the molecular mechanisms of chemoresistance and suggest potential therapeutic targets for the treatment of AML.

Conclusion: Further experimental validation of the identified miRNAs and their targets is warranted.

« Previous Next »
Graphical Abstract

[1]
Sami SA, Darwish NHE, Barile ANM, Mousa SA. Current and future molecular targets for acute myeloid leukemia therapy. Curr Treat Options Oncol 2020; 21(1): 3.
[http://dx.doi.org/10.1007/s11864-019-0694-6] [PMID: 31933183]
[2]
Luesink M. Gene expression deregulation in acute myeloid leukemia Causes, consequences, and therapeutic relevance PhD Thesis; Radboud University Nijmegen 2013.
[3]
Vetrie D, Helgason GV, Copland M. The leukaemia stem cell: Similarities, differences and clinical prospects in CML and AML. Nat Rev Cancer 2020; 20(3): 158-73.
[http://dx.doi.org/10.1038/s41568-019-0230-9] [PMID: 31907378]
[4]
Cammarata-Scalisi F, Girardi K, Strocchio L, et al. Oral manifestations and complications in childhood acute myeloid leukemia. Cancers 2020; 12(6): 1634.
[http://dx.doi.org/10.3390/cancers12061634] [PMID: 32575613]
[5]
Stubbins RJ, Stamenkovic M, Roy C, et al. Incidence and socioeconomic factors in older adults with acute myeloid leukaemia: real‐world outcomes from a population‐based cohort. Eur J Haematol 2022; 108(5): 437-45.
[http://dx.doi.org/10.1111/ejh.13752] [PMID: 35122325]
[6]
Daver N, Wei AH, Pollyea DA, Fathi AT, Vyas P, DiNardo CD. New directions for emerging therapies in acute myeloid leukemia: the next chapter. Blood Cancer J 2020; 10(10): 107.
[http://dx.doi.org/10.1038/s41408-020-00376-1] [PMID: 33127875]
[7]
Yun S, Vincelette ND, Abraham I, Robertson KD, Fernandez-Zapico ME, Patnaik MM. Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: A systematic review of hypomethylating agents trials. Clin Epigenetics 2016; 8(1): 68.
[http://dx.doi.org/10.1186/s13148-016-0233-2] [PMID: 27307795]
[8]
Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD. DNA methylation inhibitor 5-Aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol 2008; 28(2): 752-71.
[http://dx.doi.org/10.1128/MCB.01799-07] [PMID: 17991895]
[9]
Bhagat TD, Chen S, Bartenstein M, et al. Epigenetically aberrant stroma in mds propagates disease via wnt/β-catenin activation. Cancer Res 2017; 77(18): 4846-57.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0282] [PMID: 28684528]
[10]
Valencia A, Masala E, Rossi A, et al. Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine. Leukemia 2014; 28(3): 621-8.
[http://dx.doi.org/10.1038/leu.2013.330] [PMID: 24192812]
[11]
Dykes IM, Emanueli C. Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genomics Proteomics Bioinformatics 2017; 15(3): 177-86.
[http://dx.doi.org/10.1016/j.gpb.2016.12.005] [PMID: 28529100]
[12]
Liz J, Esteller M. lncrnas and micrornas with a role in cancer development. biochimica et biophysica acta (bba)-. Gene Regulatory Mechanisms 2016; 1859(1): 169-76.
[13]
Papaconstantinou IG, Manta A, Gazouli M, et al. Expression of microRNAs in patients with pancreatic cancer and its prognostic significance. Pancreas 2013; 42(1): 67-71.
[http://dx.doi.org/10.1097/MPA.0b013e3182592ba7] [PMID: 22850622]
[14]
Zhang J, Zhang K, Bi M, Jiao X, Zhang D, Dong Q. Circulating microRNA expressions in colorectal cancer as predictors of response to chemotherapy. Anticancer Drugs 2014; 25(3): 346-52.
[http://dx.doi.org/10.1097/CAD.0000000000000049] [PMID: 24304648]
[15]
Flotho C, Claus R, Batz C, et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 2009; 23(6): 1019-28.
[http://dx.doi.org/10.1038/leu.2008.397] [PMID: 19194470]
[16]
Flotho C, Sommer S, Lübbert M, Eds. DNA-hypomethylating agents as epigenetic therapy before and after allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and juvenile myelomonocytic leukemia Seminars in cancer biology. Elsevier 2018.
[http://dx.doi.org/10.1016/j.semcancer.2017.10.011]
[17]
Ru Y, Kechris KJ, Tabakoff B, Hoffman P, Radcliffe RA, Bowler R, et al. The multiMiR R package and database: integration of microRNA–target interactions along with their disease and drug associations. Nucleic Acids Res 2014; 42(17): e133.
[18]
Li H, Tian X, Wang P, Huang M, Xu R, Nie T. MicroRNA-582–3p negatively regulates cell proliferation and cell cycle progression in acute myeloid leukemia by targeting cyclin B2. Cell Mol Biol Lett 2019; 24(1): 66.
[http://dx.doi.org/10.1186/s11658-019-0184-7] [PMID: 31844417]
[19]
Sun X, Hou Z, Li N, Zhang S. MiR-597-5p suppresses the progression of hepatocellular carcinoma via targeting transcriptional enhancer associate domain transcription factor 1 (TEAD1). In Vitro Cell Dev Biol Anim 2022; 58(2): 96-108.
[http://dx.doi.org/10.1007/s11626-021-00614-1] [PMID: 35169903]
[20]
Wen HL, Xu ZM, Lin SY, Wen D, Xie JP. miR-597-3p inhibits invasion and migration of thyroid carcinoma SW579 cells by targeting RAB23. Endokrynol Pol 2021; 72(1): 22-8.
[http://dx.doi.org/10.5603/EP.a2020.0041] [PMID: 32856288]
[21]
Fu L, Shi J, Liu A, et al. A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia. Int J Cancer 2017; 140(3): 653-61.
[http://dx.doi.org/10.1002/ijc.30481] [PMID: 27770540]
[22]
Xu WP, Liu JP, Feng JF, et al. miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy. Gut 2020; 69(7): 1309-21.
[http://dx.doi.org/10.1136/gutjnl-2019-318830] [PMID: 31727683]
[23]
He Z, Shen F, Qi P, Zhai Z, Wang Z. miR-541-3p enhances the radiosensitivity of prostate cancer cells by inhibiting HSP27 expression and downregulating β-catenin. Cell Death Discov 2021; 7(1): 18.
[http://dx.doi.org/10.1038/s41420-020-00387-8] [PMID: 33462201]
[24]
Zheng Z, Zhou P, Xiao Y, Liu Q, Wan T. MiR-541-3p suppresses gastric cancer via negative regulation of HSF1. Trop J Pharm Res 2021; 20(11): 2293-8.
[http://dx.doi.org/10.4314/tjpr.v20i11.9]
[25]
Li L, Wan D, Li L, Qin Y, Ma W. lncRNA RAET1K promotes the progression of acute myeloid leukemia by targeting miR-503-5p/INPP4B axis. OncoTargets Ther 2021; 14: 531-44.
[http://dx.doi.org/10.2147/OTT.S291123] [PMID: 33500628]
[26]
Sanchez-Correa B, Bergua JM, Pera A, et al. In vitro culture with interleukin-15 leads to expression of activating receptors and recovery of natural killer cell function in acute myeloid leukemia patients. Front Immunol 2017; 8: 931.
[http://dx.doi.org/10.3389/fimmu.2017.00931] [PMID: 28824651]
[27]
Tsimberidou AM, Estey E, Wen S, et al. The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes. Cancer 2008; 113(7): 1605-13.
[http://dx.doi.org/10.1002/cncr.23785] [PMID: 18683214]
[28]
Kim DH, Xu W, Kamel-Reid S, et al. Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy. Ann Oncol 2010; 21(6): 1179-88.
[http://dx.doi.org/10.1093/annonc/mdp452] [PMID: 19875757]
[29]
Kawabata KC, Zong H, Meydan C, et al. BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells. Blood 2021; 137(6): 812-25.
[http://dx.doi.org/10.1182/blood.2019001745] [PMID: 32911532]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy