Zahra Ranjbarpoor,1,*
1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.
Introduction: Acute myeloid leukemia (AML) is an aggressive haematological malignancy characterized by abnormal proliferation and differentiation of immature myeloid cells. Despite a growing list of treatment options, most patients still relapse and die after remission, and the prognosis remains unideal. It is necessary to explore new biomarkers for diagnosis, prognostication, and therapeutic targets of AML so as to develop more effective surveillance and treatment programs. MicroRNAs (miRNAs) are small RNA molecules of approximately 22 nucleotides that bind to the 3′ untranslated region (3′-UTR) of the target mRNA and negatively regulate the expression of the target gene at the transcriptional level. miRNAs mainly participate in the pathogenesis of AML through the following five mechanisms: copy number alterations, change in the proximity to the oncogenic genomic region due to chromosomal translocation, epigenetic changes, aberrant targeting of miRNA promoter regions by altered transcription factors or oncoproteins, and finally, dysregulated miRNAs processing. This study's objective was to look at the role of microRNAs in acute myeloid leukemia.
Methods: This study on the role of microRNAs in acute myeloid leukemia used scientific databases including Science Direct, Springer, Google Scholar, and PubMed.
Results: Results showed Each AML subtype seems to exhibit a unique miRNA signature that distinguishes it from others. For example, Chen et al. reported that miR-9, an oncogenic miRNA, was overexpressed in the mixed lineage leukemia (MLL)-rearranged AML patients. Inhibition of miR-9 expression could significantly reduce cell growth/viability and promote apoptosis. Emmerich et al. found miR-9, significantly downregulated in pediatric AML with t(8;21), was characterized by its tumour-suppressive property. Upregulation of miR-9 decreased leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. Functionally, miR-9 exerted its effects by binding to let-7 to suppress the oncogenic LIN28B/HMGA2 axis. In another study, miR-9-1 was observed to be downregulated in t(8;21) AML. Besides, overexpressed miR-9-1 induced differentiation and inhibited proliferation in t(8;21) AML cell lines. MiR-10a/b was significantly increased in AML patients with t(8;21), t(9;11), NPM1 mutation, and particularly M1, M2, and M3 subtype. Abnormal high expression in those patients led to unlimited proliferation of immature blood progenitors and repressed differentiation and maturation of mature blood cells. Another study showed that miR-10a overexpression was significantly associated with French-American-British (FAB)-M3/t(15;17) subtypes and NPM1 mutation, leading to a lower percentage of bone marrow (BM) blasts, while overexpression of miR-10b was correlated with NPM1 and DNMT3A mutations, resulting in a higher percentage of BM blasts. Some studies observed overexpression of the miR-181 in cytogenetic normal AML (CN-AML) patients with CEBPA mutations, FLT3-ITD, and/or wild-type NPM1 and t(15;17). MiR-155 was upregulated in FLT3-ITD-associated AML and targeted the myeloid transcription factor PU.1. Knockdown of miR-155 could repress proliferation and induce apoptosis of FLT3-ITD-associated leukemic cells.
Conclusion: In this review, we discussed miRNAs, involving subtypes, molecular function, chemoresistance and prognosis in AML, and the interactions between major ncRNAs. Currently, the role of miRNAs in AML is most studied, but the mechanisms of microRNAs in AML still remain complex and unclear owing to miRNA target genes ranging from tens to hundreds and involving different signaling pathways.