miRNA-126 as a Biomarker for Cancer Stem Cells: Role in Chemotherapy Resistance in Iraqi Patients with Acute Myeloid Leukemia

Noorhan Sabih Al-Maliki; Zahraa Kamel  Zedan

doi:10.54133/ajms.v6i1.577

Authors

Noorhan Sabih Al-Maliki College of Biotechnology, Al-Nahrain University, Baghdad, Iraq https://orcid.org/0009-0000-6920-6283
Zahraa Kamel Zedan College of Biotechnology, Al-Nahrain University, Baghdad, Iraq https://orcid.org/0000-0002-8640-3606

DOI:

https://doi.org/10.54133/ajms.v6i1.577

Keywords:

Acute myeloid leukemia, Cancer biomarker, Chemotherapy resistance, Leukemic stem cells, miRNA-126

Abstract

Background: Acute myeloid leukemia (AML) is characterized as an aggressive blood cancer with rapid growth of immature leukemic cells. It appears that each subtype of AML displays a distinct miRNA profile. miRNAs play a role in regulating gene expression that is implicated in AML pathogenesis. Objective: This study was designed to assess the level of miRNA-126 gene expression in relation to chemotherapy resistance in various AML groups with the hope of developing a novel marker for targeted therapy and the early diagnosis and prognosis of cancer stem cells in AML patients. Methods: 120 AML cases were studied. Based on the chemotherapy stage, 40 patients were assigned to each group (newly diagnosed, under treatment, or relapsed). Baghdad Teaching Hospital, Iraq, provided the cases and samples from February 2022 to April 2023. This study also included 40 healthy controls. We used the qRT-PCR method to count the genes after setting them to the same level as a housekeeping gene (GAPDH). This method uses the ∆Ct-value and fold change (2-∆∆Ct). Results: In this study, there were significant elevated levels of miRNA-126 in AML patients compared to controls, with a higher fold change detected in the newly diagnosed group. Conclusions: The miRNA-126 upregulation is suggested to be linked to AML development and relapse, with a contribution to leukemic stem cell proliferation and treatment failure. We hypothesized that miR-126 could be an effective target for eradicating the LSC in AML.

Downloads

Download data is not yet available.

References

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. doi: 10.3322/caac.21654.

Lazarevic V, Orsmark-Pietras C, Lilljebjörn H, Pettersson L, Rissler M, Lübking A, et al. Isolated myelosarcoma is characterized by recurrent NFE2 mutations and concurrent preleukemic clones in the bone marrow. Blood. 2018;131(5):577-581. doi: 10.1182/blood-2017-07-793620.

Pabon CM, Abbas HA, Konopleva M. Acute myeloid leukemia: therapeutic targeting of stem cells. Expert Opin Ther Targets. 2022;26(6):547-556. doi: 10.1080/14728222.2022.2083957.

Sevcikova A, Fridrichova I, Nikolaieva N, Kalinkova L, Omelka R, Martiniakova M, et al. Clinical significance of microRNAs in hematologic malignancies and hematopoietic stem cell transplantation. Cancers (Basel). 2023;15(9):2658. doi: 10.3390/cancers15092658.

Zebisch A, Hatzl S, Pichler M, Wölfler A, Sill H. Therapeutic resistance in acute myeloid leukemia: The Role of Non-Coding RNAs. Int J Mol Sci. 2016;17(12):2080. doi: 10.3390/ijms17122080.

Correia NC, Barata JT. MicroRNAs and their involvement in T-ALL: A brief overview. Adv Biol Regul. 2019;74:100650. doi: 10.1016/j.jbior.2019.100650.

Su Y, Wang X, Mann M, Adamus T, Wang D, Moreira D, et al. Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo. Blood. 2020; 135:167–180. doi: 10.1182/blood.2019002045.

Yun X, Zhang Y, Wang X. Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia. Biomark Res. 2020;8:40. doi: 10.1186/s40364-020-00222-3.

Liao Q, Wang B, Li X, Jiang G. miRNAs in acute myeloid leukemia. Oncotarget. 2017;8(2):3666-3682. doi: 10.18632/oncotarget.12343.

Fletcher D, Brown E, Javadala J, Uysal-Onganer P, Guinn BA. microRNA expression in acute myeloid leukaemia: New targets for therapy? EJHaem. 2022;3(3):596-608. doi: 10.1002/jha2.441.

Zhang B, Nguyen LXT, Li L, Zhao D, Kumar B, Wu H, et al. Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nat Med. 2018;24(4):450-462. doi: 10.1038/nm.4499.

Zheng W, Zhou Y, Lu J, Xu H, Lei L, Chen C, et al. The prognostic value of miR-126 expression in non-small-cell lung cancer: a meta-analysis. Cancer Cell Int. 2017;17:71. doi: 10.1186/s12935-017-0440-8.

Lechman ER, Gentner B, Ng SW, Schoof EM, van Galen P, Kennedy JA, et al. miR-126 Regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell. 2016;29(2):214-228. doi: 10.1016/j.ccell.2015.12.011.

de Leeuw DC, Denkers F, Olthof MC, Rutten AP, Pouwels W, Schuurhuis GJ, et al. Attenuation of microRNA-126 expression that drives CD34+38- stem/progenitor cells in acute myeloid leukemia leads to tumor eradication. Cancer Res. 2014;74(7):2094-2105. doi: 10.1158/0008-5472.CAN-13-1733.

Shibayama Y, Kondo T, Ohya H, Fujisawa S, Teshima T, Iseki K. Upregulation of microRNA-126-5p is associated with drug resistance to cytarabine and poor prognosis in AML patients. Oncol Rep. 2015;33(5):2176-2182. doi: 10.3892/or.2015.3839.

Almohsen F, Al-Rubaie HA, Habib MA, Nasr SA, Perni R, Al-Quraishi L. Circulating miR-126-3p and miR-423-5p expression in de novo adult acute myeloid leukemia: Correlations with response to induction therapy and the 2-year overall survival. J Blood Med. 2022;13:83-92. doi: 10.2147/JBM.S347397.

Zhang L, Nguyen LXT, Chen YC, Wu D, Cook GJ, Hoang DH, et al. Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance. Nat Commun. 2021;12(1):6154. doi: 10.1038/s41467-021-26420-7.

Amal M. Cytogenetic Study of Leukemic Stem Cells in a sample of Iraqi Patients with Acute Myeloid Leukemia, PhD Thesis, College of Biotechnology, Al-Nahrain University; 2021.

Dorrance AM, Neviani P, Ferenchak GJ, Huang X, Nicolet D, Maharry KS, et al. Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. Leukemia. 2015;29(11):2143-2153. doi: 10.1038/leu.2015.139.

Levin M, Stark M, Ofran Y, Assaraf YG. Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance. Cancer Cell Int. 2021;21(1):53. doi: 10.1186/s12935-021-01746-w.

van Gils N, Denkers F, Smit L. Escape from treatment; the different faces of leukemic stem cells and therapy resistance in acute myeloid leukemia. Front Oncol. 2021;11:659253. doi: 10.3389/fonc.2021.659253.

Ding Y, Gao H, Zhang Q. The biomarkers of leukemia stem cells in acute myeloid leukemia. Stem Cell Investig. 2017;4:19. doi: 10.21037/sci.2017.02.10.

Smith P, Syed N, Crook T. Epigenetic inactivation implies a tumor suppressor function in hematologic malignancies for Polo-like kinase 2 but not Polo-like kinase 3. Cell Cycle. 2006;5(12):1262-1264. doi: 10.4161/cc.5.12.2813.

Nguyen LXT, Zhang B, Hoang DH, Zhao D, Wang H, Wu H, et al. Cytoplasmic DROSHA and non-canonical mechanisms of MiR-155 biogenesis in FLT3-ITD acute myeloid leukemia. Leukemia. 2021;35(8):2285-2298. doi: 10.1038/s41375-021-01166-9.

Cammarata G, Augugliaro L, Salemi D, Agueli C, La Rosa M, Dagnino L, et al. Differential expression of specific microRNA and their targets in acute myeloid leukemia. Am J Hematol. 2010;85(5):331-339. doi: 10.1002/ajh.21667.

Li Z, Chen P, Su R, Li Y, Hu C, Wang Y, et al. Overexpression and knockout of miR-126 both promote leukemogenesis. Blood. 2015;126(17):2005-2015. doi: 10.1182/blood-2015-04-639062.

Zhang B, Pei Z, Wang H, Bai J, Wang J, Zhao Y, et al. Clinical value of serum miRNA in patients with acute promyelocytic leukemia. J Oncol. 2022;2022:7315879. doi: 10.1155/2022/7315879.