High expression of miR-25 predicts favorable chemotherapy outcome in patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is a group of clonal malignant diseases that derive from the hematopoietic stem cells. AML is characterized by a large group of germinal cells, which leads to a loss of normal hematopoietic function [1]. The clinical prognosis of patients with AML is various. The differences in outcomes among AML patients depend on multiple intrinsic factors [2, 3]. With the development of methodologies of massive sequencing, it has been demonstrated that somatic mutations in NPM1, FLT3, CEBPA, IDH1 and IDH2 are connected to prognosis in AML [4]. To be specific, patients with mutated FLT3 have a dismal outcome, while mutations in NPM1 and CEBPA are related with favorable prognosis. The advent of chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has significantly improved AML treatment outcomes [5]. Relapse and refractory of leukemia remain the most disturbing problems in AML patients [6]. Thus, it is urge to explore more reliable and effective prognostic biomarkers to enhance the capacity of prediction and thus improve the outcome of AML by choosing optimal therapeutic approach.

MicroRNAs are short non-coding RNAs, which are implicated in a diverse group of critical cellular mechanisms, such as apoptosis, differentiation, cell cycle progression, and immune responses [7]. Recently, more and more attentions have been focused on the prognostic role of microRNAs in AML. A recent study has shown that the upregulation of miR-181a facilitates better survival of AML patients who are cytogenetically normal [8]. However, AML patients who are cytogenetically normal and upregulated miR-212 and miR-3151 have shorter overall and disease-free survival [9, 10]. However, most microRNA analyses did not differentiate the AML patients treated with chemotherapy and allo-HSCT. Thus, microRNAs may have varied prognostic roles in chemotherapy and allo-HSCT treatment group, respectively.

MiR-25, a member of miR-106b-25 cluster, is located on human chromosome 7q22.1 [11]. Previous studies revealed that miR-25 was involved in many kinds of cancers [12]. It has been identified that miR-25 is a potential biomarker for pediatric AML based on Pipeline of Outlier MicroRNA Analysis (POMA) model [13]. More important, Garzon et al. [14] reported that miR-25 is significantly down-regulated in 122 newly diagnosed AML samples compared with CD34⁺ normal cells. However, clinical and prognostic role of miR-25 in AML are still unclear. A total of 162 recently diagnosed de novo AML patients were enrolled in this evaluation. The cases were placed into two groups based on the treatment that they received. The present study suggested that miR-25 is a solitary AML prognostic biomarker. Furthermore, our study revealed that allo-HSCT would be more beneficial to patients showing downregulated miR-25.

AML has been considered to occur as the result of genetic abnormalities, including chromosomal rearrangements, gene deregulations and mutations [23]. The deregulated expression of microRNAs in AML can influence cell proliferation, survival and hematopoietic differentiation [24]. The association of microRNAs with prognosis in heterogeneous patients with AML is still largely unclear. In this evaluation, the upregulated of miR-25 was determined to be an independently favorable prognosticator of AML cases who were administered chemotherapy. Furthermore, allo-HSCT may overcome the poor prognosis of AML cases with low miR-25 expression.

A correlation between aberrant miRNA expression and AML prognosis has been established [25, 26]. However, most of previous microRNA markers is restricted to AML without cytogenetic abnormalities. In our study, univariate and multivariate analyses demonstrated that miR-25 is an independently biomarker for cases administered chemotherapy. High miR-25 expression can predict favorable outcome. The prognostic role of miR-25 is different with previously established prognostic factors in a heterogeneous population of AML. MiR-25, as an independent outcome predictor, may improve the current clinical risk-based classification of patients with AML.

To further understand the biological insight into the molecular mechanism underlying miR-25, we identified genes significantly correlated with miR-25 expression. We discovered that the expression of miR-25 negatively connected with the levels of PRDM16, HOXAs, HOXBs, MEIS1, CD97, IRAK1, NFKB2 and MYH9. HOXA and HOXB gene clusters are the common characters of AML [27, 28]. Of these genes, HOXB4 is positively involved in the renewal of hematopoietic stem cell [29, 30]. A previous study has shown that HOXA9 contributes to the proliferation, apoptosis, and differentiation processes of leukemia [31]. In addition, HOXA9 has been correlated with poor AML prognosis [32]. Prior evaluations have revealed that IRAK1 may be utilized as a therapeutic target for AML, and TRAF6 may be used to activate pathways such as NFKB, MAPK, and AKT [20, 33]. PRDM16, also known as MEL1, is highly homologous to MDS1/EVI1. High expression of PRDM16 can predict the adverse outcome of AML [18]. Moreover, MYH9 has also been predicted as a direct target of miR-25. High expression of MYH9 can induce resistant to chemotherapy and predict poor clinical outcome in AML [22]. Taken together, the miR-25-associated gene-expression profiling analyses provide insights into the leukemogenic role of genes that are either direct or indirect targets of miR-25. Therefore, the miR-25-associated gene-expression signature analysis give novel insights into the oncogenic role of these genes. These miR-25-related genes could contribute to the chemotherapeutic responses of AML patients.

The FMS-like tyrosine kinase 3 (FLT3) gene is pivotal to hematopoietic stem cell proliferation and differentiation [34]. FLT3 mutations take a great account of most frequent genetic aberrations in AML [35]. FLT3-ITD mutation is one of FLT3 mutations, which can keep the tyrosine kinase persistently active, and result in the abnormal proliferation of leukemic cells. Mutations in the FLT-ITD gene have been associated with higher risk for relapse and poor OS and EFS [36]. Consistent with the conclusion, our data suggested that FLT3-ITD mutation is a poor outcome marker in patients undergoing allo-HSCT. These analysis results indicate that allo-HSCT cannot overcome all adverse prognosis of molecular markers. The findings of this study have revealed that allo-HSCT circumvents the poor chemotherapy outcomes that are related to downregulated miR-25 expression. Thus, low miR-25 expression may be employed as a predictor of adverse prognoses among patients who received chemotherapy, as well as identify patients who require strategies in selecting the best treatment regimen, i.e., chemotherapy and/or allo-HCST.

In conclusion, high expression of miR-25 was identified to independently predict favorable survival in a highly heterogeneous population of patients with AML. Our findings may offer more information for the therapeutic strategies and the prediction of patients with AML, which may improve the survival and reduce the relapse of them. More importantly, allo-HSCT circumvents poor chemotherapeutic outcomes in cases with downregulated miR-25. The expression levels of miR-25 may thus be utilized in determining whether chemotherapy or allo-HSCT is the optimal treatment regimen for a specific AML patient.