Abstract
Objective: MicroRNAs (miRNAs) are small noncoding RNA molecules that participate in vital cell processes such as proliferation, apoptosis, and differentiation. In recent years, they have been proven to play vital roles in haematological malignancies. In this review we briefly introduce some basic knowledge of microRNAs and summarize their ectopic expression in haematological malignancies, especially in leukaemia. We will also discuss the potential of microRNAs in the diagnosis of leukaemia, in the determination of the clinical prognosis of diverse subtypes, and in targeted therapy.
Discussion: Despite current adoption of novel biological agents combining traditional chemotherapy regimens, leukaemia remains to have undesirable clinical outcomes due to inaccurate diagnosis, invasiveness of the disease, and patients’ intolerance to chemotherapy, thus brand new therapeutic directions are urgently needed. MiRNAs regulate gene expression by means of binding to the 3'-untranslated regions of corresponding mRNAs, leading to the degradation of targeted mRNA or the inhibition of translation. It has been confirmed that they can either function as tumour inhibitors, or may trigger tumourigenesis in certain situations, this specific dual characteristic undoubtedly attract scientists to explore their roles in haematological malignancies. It is of great necessity to summarize the roles of miRNAs in haematological malignancies diagnosis, prognosis evaluation, and clinical treatment.
Conclusions: Future studies may take full advantage of miRNAs detection in diagnosing, in choosing targeted biological therapy, and in avoiding predictable side effect, thus the overall survival rate and cure efficiency of leukaemia should improve.
Introduction
MicroRNAs (miRNAs) are a class of small, noncoding RNA molecules of 18–25 nucleotides in length that regulate approximately 30% of all protein-coding RNAs.Citation1 They regulate gene expression by the induction of mRNA degradation or the inhibition of translation by binding to the 3'-untranslated regions of target mRNAs. MiRNAs take part in various biologic processes that involve development, proliferation, apoptosis, and differentiation and have been proven to act as both oncogenes and tumour suppressors.Citation2,Citation3 MicroRNA biogenesis begins in the nucleus, and genomic sequences that code for miRNAs are transcribed by RNA polymerase II to form primary miRNA transcripts (pri-miRNAs).Citation4 Pri-miRNAs are further cleaved within the nucleus by means of the ‘microprocessor complex’, which consists of Drosha, an RNA processing enzyme, and its co-factor DiGeorge syndrome critical region gene 8, to form a 60- to 110-nucleotide hairpin structure (pre-microRNA).Citation5 The pre-miRNAs are then actively transported to the cytoplasm by Exportin 5Citation6 and are cleaved by DICER1 (Dicer) into mature miRNAs before being loaded into the RNA-induced silencing complex.Citation7
Upon receipt of the proper signals, haematopoietic stem cells can rapidly differentiate into blood cells of distinct lineages while maintaining their pluripotency. The entire process is tightly controlled by a complex network of stimuli from inner and outer spaces, transcription factors, cytokines, signalling pathways and many other important biological molecules. It has been shown that miRNAs specifically target many of these factors and thus play vital roles in the process of haematopoiesis.Citation8
Hundreds of miRNAs have been proven to be involved in the process of stem cell self-renewal and differentiation, and their expression may differ greatly in various lineages. It was observed in one study that miR-17, -24, -146, -155, -128, and -181 can block the early differentiation of haematopoietic cells into more mature forms, and miR-16, -103, and -107 may block the differentiation of later progenitor cells, whereas miR-221, -222, and -223 control the terminal stages of haematopoietic differentiation.Citation8 Their abnormal expression obviously leads to the accumulation of immature progenitor cells, which may be one of the mechanisms of tumourigenesis. The members of the miR-125 family have been shown in several groups and are over-expressed in haematopoietic stem and progenitor cells, and their expression decreases upon differentiation.Citation9 Several recently discovered miRNAs are lineage specific. For example, GATA-1 activates the transcription of miR-451 and leads to the down-regulation of c-Myc, which is a transcription factor and oncogene that is involved in the self-renewal of haematopoietic stem cells. As a result, the progenitor cells differentiate into the erythroid lineage.Citation10 In the lymphoid lineage, as an important regulator, the deletion of the miR-17-92 cluster leads to an increase in the expression of the pro-apoptotic protein Bim in B cells, which prevents pro- to pre-B cell development.Citation11
Over the years, various methods have been used to detect ectopic expression in human diseases, including haematological malignancies. Links between genomic localizations of miRNAs and cancer-associated genomic-regions (CAGRs) enlightening scientists to discover their involvement in cancers for the first time. Joshi D pointed out that a high proportion of miRNA genes are encoded in the CAGRs, fragile sites, and regions concerning loss of heterozygosity and amplification.Citation12 The miRNA signature can be used in the diagnosis of diseases and can even be used to distinguish between myeloid and lymphoid tumour lineages. They can also function as prognostic indicators of haematological disease and can be used to differentiate high-risk, immediate-risk, and low-risk cancers. Their specific dual characteristics as both an oncogene and a tumour suppressor has led scientists to create tools for future therapeutic intervention, such as antagomirs or miRNA restoration techniques. This review mainly introduces the ectopic expression of miRNAs in leukaemia and their role in diagnosis, prognosis, evaluation, and targeted therapy.
The role of miRNAs as novel biomarkers in the diagnosis of leukaemia
Many patients do not have symptoms during the early stages of disease, it is therefore of great necessity to identify predictive biomarkers to detect their changes in the early stages of disease and to take forceful action. Numerous studies have investigated the potential value of circulating miRNAs for the detection of leukaemia.
| (1) | miRNAs as biomarkers in acute myeloid leukaemia (AML) | ||||
Four major rearrangements in AML are the t (8;21), inv (16), t (15;17), and MLL/11q23 translocations, which account for about 30% of all AML cases, the World Health Organization has adopted them as the criteria for subclassification of AML. In a cohort of 100 primary AMLs, those with the t(15;17) translocation were validated to have specific up-regulation of seven miRNAs located on the human 14q32–imprinted domain, the set included miR-127, miR-154, miR-154*,miR-299, miR-323, miR-368, and miR-370.Citation14 In a large-scale genome-wide miRNA profiling study of patients with AML, miR-126/126* was found to be specifically over-expressed in both t(8;21) and inv(16) samples, whereas miR-224, miR-368, and miR-382 were almost exclusively over-expressed in the t(15;17) samples. Studies have also shown an association between the differential expression of miR-126/126* and the partial promoter demethylation status of the 287-bp CpG island. It was confirmed that miR-126 inhibited apoptosis and increased cell viability both in AML cells and mouse normal bone marrow progenitor cells, either alone or cooperated with the t (8;21) fusion gene. PLK2 was also verified to be a target of miR-126.Citation15 Other studies have indicated that let-7b and let-7c were down-regulated in AML with t (8;21) and inv (16), this regulation might be associated with over-expression of RAS.Citation16
Several gene mutations have also been shown to play important roles in the generation of AML. Amongst them, the KIT, FLT3-ITD, and CEBPA mutations are the most frequently mentioned. Several studies have confirmed the characterization of AML by aberrant KIT tyrosine kinase activity. It has been found that miR-29b took part in a complex network related to the interacting transcription factors SP1 (specificity protein1) and NF-ĸB as well as histone deacetylases, and leading to the over-expression of KIT. This autoregulatory loop eventually caused leukaemogenesis.Citation17 FLT3-ITD is often viewed as a poor marker for prognosis in patients with AML, and miR-155 over-expression has consistently been reported in adult and paediatric patients with FLT3-ITD AML, which implied special links between them.Citation18,Citation19 Several trials have demonstrated that CEBPA triggers the expression of miR-223 in patients with AML. MiR-223 inhibited myeloid progenitor proliferation and promoted differentiation by targeting Mef2c and E2F1. This may partly explain why the down-regulation of miR223 and subsequent interference of myelopoiesis were often observed in patients with AML with mutated CEBPA.Citation20,Citation21,Citation22 It was also pointed out that the CEBPA/miR-34a/E2F3 axis could be another mechanism of differentiation blocking in CEBPA-mutant AMLsCitation22 (Table ).
| (2) | miRNAs as biomarkers in acute lymphoid leukaemia | ||||
Table 1 Ectopic expression of miRNAs in AML concerning cytogenetic translocations and gene mutations
| (3) | miRNAs as biomarkers in chronic myeloid leukaemia (CML) | ||||
Table 2 Ectopic expression of miRNAs in ALL
| (4) | miRNAs as biomarkers in chronic lymphoid leukaemia | ||||
By application of both cloning methods and analysis by quantitative real-time reverse-transcription polymerase chain reaction, Valerio identified five miRNAs with differential expression between the CLL samples and the controls. Amongst them, miR-21 and miR-155 appeared to be significantly over-expressed in almost every CLL sample analysed. It has been acknowledged that patients with CLL usually have different clinical courses, this clinical heterogeneity originates in part from the different mutational statuses of the immunoglobulin variable genes (IgVH), ZAP-70 expression, and specific cytogenetic alteration. In line with previous viewpoints, Valerio's study found an over-expression of miR-150, miR-223, miR-29b, and miR-29c in the CLL cases with IgVH mutation as compared to those without IgVH mutation. As indicated previously, hypermutation of the IgVH genes often implied relatively stable disease, whereas an unmutated IgVH configuration accompanied a more aggressive clinical course. Thus the miRNAs mentioned above were closely associated with biological features containing known implications for prognostic factors and may prove to be useful in patient stratification.Citation38 In clinical studies, patients with CLL who have TP53 mutations and 17p deletions are usually placed in a chemotherapy-refractory group. As a result, scientists have been searching for related miRNAs that might link to such mutations. One study discovered that the 17p13/p53 deletion was associated with the down-regulation of miR-34a expression in patients with B-ALL, which suggested that the down-regulation of miR-34a might also be responsible for chemotherapy resistance and could serve as a marker for poor prognosis in patients with CLLCitation39 (Table ).
Table 3 Ectopic expression of miRNAs in other types of leukaemia (CML and CLL)
The significance of miRNAs in predicting the prognosis of leukaemia
In the diagnosis of a specific type of leukaemia, several parameters have been used to evaluate their prognosis, such as karyotype analysis, immunohistochemical analysis, and so on. Upon the discovery of various types of miRNAs in relation to haematopoietic malignancies, scientists have devoted themselves to studying the possibility of combining microRNA signature detection with the prevalent experimental practices in the prediction of the clinical prognosis of specific cases of leukaemia.
In a clinical trial of 86 patients with a new diagnosis of AML, the down-regulation of miR-96 in AML was associated with higher white blood cell counts and bone marrow blast counts and with lower haemoglobin and platelet counts, which reflected a strong relationship between miR-96 suppression and aggressive clinical features. The study also discovered that patients with low expression of miR-96 showed worse relapse-free survival rates and overall survival rates, which indicated a poorer prognosis for AML.Citation40 High levels of MiR-335 expression were found in the bone marrow samples of paediatric patients with AML in several studies, and it was further demonstrated that a high serum level of miR-335 was correlated with the aggressive clinical features, and its up-regulation was most commonly observed in the FAB classification subtype M7 and associated with unfavourable cytogenetic risks.Citation41 MiR-124-1 was frequently down-regulated in patients with AML, and it was confirmed that amongst the patients who received complete remission, those who had miR-124-1 under-expression had longer overall survival rates and relapse-free survival rates than those without miR-124-1 under-expression. This finding indicated that the down-regulation of miR-124-1 might have a favourable effect on the prognosis of AML.Citation42
To determine the expression profile of paediatric ALL, Karolina collected samples from 51 children with diagnoses of ALL and found that increased expression of miR-128b expression and decreased expression of miR-223 could contribute to cell proliferation and survival, that the expression level of miR-223 would recover to a normal level during treatment, and that its down-expression could be a predictor of relapse. The study also found that increased expression of miR-128b correlated with a better prognosis, this finding would be useful in the pretreatment selection of patients with poor prognosis and might be of great significance in the adoption of more effective treatments.Citation43
MiRNAs also present prognostic significance in CML samples. Edurne identified that miR-191, miR-29a, miR-422b, miR-100, miR-326, miR-26a were promising predictors of imatinib resistance in newly diagnosed CML patients.Citation44 In another research, miR-17-92 cluster was discovered to be up-regulated in the chronic phase but not during blast crisis of chronic myeloid leukaemia, their expression decreased upon imatinib treatment in CML cell lines, indicating a control of the chronic phase by these miRNAs.Citation45 In a study concerning the activities of miR-328 in myeloid cell differentiation and survival, Eiring reported that low expression of miR-328 in CML was associated with progression to the blast crisis phase of the disease.Citation46 When analysing correlation between microRNA expression and CML prognosis, Stephane found that miR-142-3p correlated to the Sokal score, and the rapid inhibition of miR-18 during imatinib treatment was detrimental to an early haematologic remission, suggesting that miRNAs might serve as novel clinically useful biomarkers in CMLCitation47 (Table ).
Table 4 MiRNAs in relation to predicting prognosis of leukaemia
The role of microRNA in therapeutic application
It has been said that all of the current efforts in the study of tumour are paving the way for the discovery of more effective treatments for the fight against fierce diseases that threaten the health of human beings. Therefore, the most promising clinical aspect of miRNAs is their application in targeted therapy. Because miRNAs can function as both oncogenes and tumour suppressors, their therapeutic directions can be divided into at least two groups: the use of miRNA mimics to restore the physiological expression of miRNAs that are down-regulated and the use of miRNA inhibitors targeted against over-expressed miRNAs.
| (1) | Creation of miRNA mimics to re-express down-regulated miRNAs. | ||||
Many microRNA restoration techniques are undergoing clinical trials. The siRNAs and shRNAs are the hottest. It has been recognized that siRNAs resemble the mature miRNA duplex, and in fact, the two have been shown to be functionally substitutable against target mRNAs in several clinical trials. Therefore, the introduction of synthetic siRNA-like molecules that mimic the Dicer-processed miRNA duplex is a potential method for the rescue of under-expressed miRNAs.Citation52 The major challenge today remains tissue-specific and cell-type-specific targeting, therefore future studies should focus on the invention of cell-specific siRNAs that target cell-surface receptors.Citation53,Citation54 The Pol III-driven shRNA system is another attractive method for the restoration of the expression of miRNAs because they can express the mature miRNA form, moreover, their well-defined transcription start and termination sites ensure abundant expression, which leads to effective target knockdown.Citation55
| (2) | Using interference-type strategies to silence up-regulated miRNAs | ||||
Modified antisense oligonucleotides, also referred to as ‘antagomirs’ for their miRNA inhibition properties, are currently the most promising tools for miRNA intervention, and several studies have used different modifications of these antisense oligos to successfully inhibit miRNA expression in cell culture. Anti-miRNA oligonucleotides are a common type of antagomir, they are synthesized into single-stranded antisense oligonucleotides that consist of 17–22 nucleotides and inhibit the interaction between miRNAs and their diverse targets. Even so, anti-miRNA oligonucleotides have drawbacks regarding their inability to bind more than one miRNA.Citation58 As another group of antagomirs, microRNA sponges can bind to the targeted miRNAs at more than one point. They interact with the corresponding miRNA and prevent its interaction with the target mRNA.Citation59 MicroRNA masking is another strategy to prevent miRNA-mRNA binding. In contrast to the methods described above, this technique binds directly to the target miRNA-binding site in the 3'-untranslated regions of its mRNA target, thus preventing miRNAs from binding to it and preventing the function of miRNAs.Citation60
| (3) | Other indirect strategies | ||||
In a group of 353 patients with diagnoses of ALL, the expression of miR-124a was down-regulated by hypermethylation of the promoter and histone modifications, thus inducing the up-regulation of its target, CDK6, and phosphorylation of retinoblastoma and leading to the abnormal proliferation of ALL cells. The use of CDK6 inhibitors could decrease ALL cell growth in vitro, whereas the over-expression of pre-miR124a led to decreased tumourigenicity in an in vivo mouse model.Citation61 These findings exhibit the possibility of new therapeutic strategies for patients with ALL, either by the use of drugs that inhibit methylation and histone modifications or by directly targeting the CDK6 protein, and their combination may be a better choice.
Conclusions
The details discussed in this review demonstrate that miRNAs are not only involved in the normal process of haematopoiesis, but also play important roles in the pathogenesis of leukaemia. Their specific expression in leukaemia allows them to be used as novel biomarkers to differentiate the various types of leukaemia, to make more accurate diagnoses and furthermore, to estimate clinical prognoses before the development of an individualized treatment plan. The association between the ectopic expression of miRNAs and leukaemogenesis has already been viewed as a new avenue for treatment. However, because the technique is almost completely new, many obstacles still need to be settled before it can be put into practice, including the effective targeting of therapy, such as tissue-specific delivery, dosage and pharmacodynamics problems and several safety concerns such as those concerning off-target effects, RNA-mediated immunostimulation and the use of viral vectors. Moreover, some of the miRNAs may act as both oncogenes and tumour suppressors in different contexts. For example, the miR-17-92 cluster of miRNAs function in totally opposite ways in different tissues, and if it is not controlled well, targeted therapy in one tissue or system must aggravate abnormal function in others. This emphasizes the need for a better understanding of the expression patterns and potential roles of the expression of specific miRNAs in other tissues to avoid undesirable side effects. Once this field is exploited fully in the future, the overall survival rate and cure efficiency of leukaemia should improve.
Disclaimer statements
Contributors None.
Funding The work was supported by a grant from National Natural Science Funds of China (No:81270626).
Conflict of interest The authors declare no competing financial interests.
Ethics approval None.
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