Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

MiR-425 expression profiling in acute myeloid leukemia might guide the treatment choice between allogeneic transplantation and chemotherapy

MiR-425 expression profiling in acute myeloid leukemia might guide the treatment choice between... Background: Acute myeloid leukemia (AML) is a highly heterogeneous disease. MicroRNAs function as important biomarkers in the clinical prognosis of AML. Methods: This study identified miR-425 as a prognostic factor in AML by screening the TCGA dataset. A total of 162 patients with AML were enrolled for the study and divided into chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT ) groups. Results: In the chemotherapy group, patients with high miR-425 expression had significantly longer overall survival (OS) and event-free survival (EFS) compared with patients with low miR-425 expression. In multivariate analyses, high miR-425 expression remained independently predictive of a better OS (HR = 0.502, P = 0.005) and EFS (HR = 0.432, P = 0.001) compared with patients with low miR-425 expression. Then, all patients were divided into two groups based on the median expression levels of miR-425. Notably, the patients undergoing allo-HSCT had significantly bet - ter OS (HR = 0.302, P < 0.0001) and EFS (HR = 0.379, P < 0.0001) compared with patients treated with chemotherapy in the low-miR-425-expression group. Mechanistically, high miR-425 expression levels were associated with a profile significantly involved in regulating cellular metabolism. Among these genes, MAP3K5, SMAD2, and SMAD5 were predicted targets of miR-425. Conclusions: The expression of miR-425 may be useful in identifying patients in need of strategies to select the opti- mal therapy between chemotherapy and allo-HSCT treatment regimens. Patients with low miR-425 expression may consider early allo-HSCT. Keywords: miR-425, Acute myeloid leukemia, Prognosis, Chemotherapy, Allo-HSCT *Correspondence: msniu24@126.com; lihmd@163.com Chen Yang, Tingting Shao and Huihui Zhang contributed equally to this work Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. J Transl Med (2018) 16:267 Page 2 of 11 allo-HSCT and chemotherapy is largely unknown. There - Background fore, the predictive microRNAs for the early and accurate Acute myeloid leukemia (AML) originates from prolif- identification of optimal therapy in patients with AML erative, clonal, and occasionally poorly differentiated cells may help improve the clinical individual therapy. of the hematopoietic system [1]. AML is the most com- In this study, miR-425 was identified as a prognostic mon malignant myeloid disease in adults, accounting for factor in AML independent of other strong molecular 80% of adult leukemia [2]. Patients with AML showed predictors using genome-wide screening. A total of 162 heterogeneous outcomes after receiving different treat - patients newly diagnosed with AML were divided into ments, partly depending on patient age, karyotype, and two groups based on the allo-HSCT and chemotherapy mutational status. Conventional cytotoxic chemotherapy treatment types. The prognostic role of miR-425 was ana - is the first-line treatment option for patients with AML. lyzed in allo-HSCT and chemotherapy groups. A gene Allogeneic hematopoietic stem cell transplantation (allo- expression signature associated with miR-425 expression HSCT) offers strong anti-leukemic effect and potentially was derived in patients with AML to investigate biologic curative treatment in high-risk AML [3]. The progno - insights. sis of AML largely depends on treatment response and cytogenetic characteristics. Thus, the clinical and genetic prognostic markers are crucial in evaluating patients with AML and in guiding rational management. Methods Cytogenetics and molecular genetics were used for Patients stratifying patients with AML into favorable, intermedi- A total of 162 patients newly diagnosed with AML were ate, and adverse prognostic risk groups [4]. Prognostic recruited in this study. Seventy-two patients accepted stratification in cytogenetically normal AML was mainly allo-HSCT, and the remaining only accepted chemother- based on the mutational status of NPM1, FLT3, and apy (with 3  days of an anthracycline and 7  days of cyta- CEBPA [5]. Patients with FLT3-ITD, RUNX1, ASXL1, rabine). All data sets are publicly available in the TCGA and TP53 mutations were classified into the adverse risk database. According to the Declaration of Helsinki, all group [5]. The decision to perform allo-HSCT depended participants included in this study signed the written on the assessment of the risk–benefit ratio based on informed consent, and the study was approved by the cytogenetic and molecular genetic features. Patients with human studies committee of Washington University. The high-risk genetics were recommended to undergo allo- whole-genome and whole-exome sequencing analyses HSCT. However, patients with FLT3-ITD, TP53, and were performed to detect the mutational spectrum of WT1 mutations still had poor outcome and high relapse patients with AML. The mRNA and miRNA sequencing rate even after allo-HSCT as a post-remission therapy. were performed to analyze the expression of mRNAs and Currently, prognosis and optimal post-remission ther- miRNAs. All clinical, molecular and cytogenetic infor- apy cannot be predicted precisely in many subgroups of mation are publicly accessible from the TCGA website. patients with AML [6, 7]. Therefore, novel prognostic markers are urgently needed to identify which patients are best suited for chemotherapy and who should be Gene expression profiling offered allo-HSCT. Of the 162 patients, 155 had both microRNA and mRNA MicroRNAs play important roles in modulating cellu- expression data. These patient samples were used for lar behaviors by binding to the 3′-untranslated regions of identifying the gene expression profile associated with their target mRNAs. MicroRNAs regulate the expression miR-425 expression. For microRNA-seq data, read of intracellular proteins. They act as epigenetic regula - counts for each sample were normalized to reads per mil- tors and influence the self-renewal and differentiation of lion. For expression profiling, the expression values were leukemia stem cells [8]. Furthermore, the dysregulation logged (base 2) before analysis. A comparison of mRNA of microRNA expression has been shown to be associ- expression was made between patients with high and ated with the clinical outcome of patients with AML. low microRNA expression. Finally, gene rows were reor- MiR-181a has been confirmed to be associated with the dered using a hierarchical clustering analysis. The online favorable clinical outcome of patients with cytogeneti- applications miRBase Targets Version 7 and Targetscan cally normal AML [9]. High miR-212 expression is inde- Release 7.1 were used for the in silico target prediction of pendently predictive of favorable survival in AML [10]. microRNAs. The gene/microRNA expression signatures In contrast, high miR-3151 expression was identified as were derived by Spearman correlation analysis. Gene an unfavorable prognosticator for patients with AML ontology enrichment analysis of genes in miR-425-asso- [11]. However, the relevance of microRNAs as predictive ciated signature was conducted using the Database for molecular markers to guide the treatment choice between Annotation, Visualization, and Integrated Discovery. Yang et al. J Transl Med (2018) 16:267 Page 3 of 11 Definition of clinical endpoints and statistical analysis blast, PB blast, NPM1, DNMT3A, RUNX1, MLL-PTD, Overall survival (OS) was measured from the date of IDH1, IDH2, and TP53 between high- and low-miR-425 diagnosis to the date of death at the last follow-up. Event- expression groups. free survival (EFS) was measured from the date of diag- nosis to the date when the first adverse event, including Prognostic value of miR‑425 in patients relapse and death, occurred. Pearson Chi square and with chemotherapy and allo‑HSCT treatment Fisher’s exact tests were used for categorical variables. Kaplan–Meier curves and log-rank test were used to test The Mann–Whitney U test was performed for analyzing for differences in survival distribution so as to investigate continuous variables. Estimated distributions of OS and the prognostic role of miR-425 in patients with AML. In EFS were calculated using the Kaplan–Meier method, the chemotherapy group, the survival distribution curves and the log-rank test was used to compare differences showed that patients with high miR-425 expression had between survival curves. In univariate and multivariate significantly longer OS (P = 0.0024) and EFS (P = 0.0004) analyses, Cox proportional hazards models were used to compared with patients with low miR-425 expression test the relationship between survival and miR-425. The (Fig.  1a, b). However, no significant differences were hazard ratio (HR) and its 95% confidence interval (CI) found between high- and low-miR-425-expression were assessed using the Cox proportional hazards model. groups in patients undergoing allo-HSCT (Fig.  1c, d). All statistical tests were performed as two sided, and a P These data suggested that high expression of miR-425 value < 0.05 was considered statistically significant. SPSS specifically predicted a favorable outcome in patients software 18.0 and GraphPad Prism software 6.0 were with AML treated with chemotherapy. used for the statistical analysis in this study. MiR‑425 was independently associated with a clinical Results outcome in AML Associations of miR‑425 expression with clinical Univariate and multivariate analyses were performed and molecular features to assess the value of miR-425 in predicting the OS and Details on the molecular and clinical characteristics EFS of patients with AML. In the chemotherapy group, of the patients are summarized in Table  1. Pearson Chi the univariate analysis showed that the high expres- square test, Fisher’s exact test, and Mann–Whitney U sion of miR-425 had a prognostic value for predict- test were performed to investigate the associations of ing EFS (HR = 0.449, 95% CI = 0.279–0.721, P = 0.001) miR-425 with clinical and molecular characteristics. and OS (HR = 0.506, 95% CI = 0.316–0.811, P = 0.005). The median expression level of miR-425 was used to In the multivariate analysis, miR-425 and several well- define high- and low-miR-425-expression groups. In the known prognostic factors were included into the model chemotherapy group, patients with low miR-425 expres- (Table 2). High miR-425 remained independently predic- sion were more often diagnosed with M0 compared with tive of longer EFS (HR = 0.432, 95% CI = 0.266–0.703, patients with high miR-425 expression (P = 0.006). More- P = 0.001) after adjusting for TP53 (P = 0.004) and over, patients with higher miR-425 expression in the CEBPA (P = 0.034). High miR-425 expression was also chemotherapy group had a lower BM (P = 0.050) and PB independently predictive of longer OS (HR = 0.502, 95% blast (P = 0.002) counts. Patients with miR-425 upregu- CI = 0.311–0.811, P = 0.005) after adjusting for the P53 lation included more good risk cases (P = 0.002). AML mutational status (HR = 2.519, 95% CI = 1.286–4.933, is a complex disease, characterized by multiple somati- P = 0.007). cally acquired driver mutations. Genetic abnormali- In the allo-HSCT group, the univariate analysis ties are powerful prognostic factors for AML. Thus, we showed that patients with MLL-PTD had shorter EFS analyzed if miR-425 expression associated with the gene (HR = 6.028, P = 0.001) and OS (HR = 3.106, P = 0.032). mutation status. Patients with higher miR-425 expression FLT3-ITD was unfavorable for both EFS (HR = 1.873, often had more CBFβ-MYH11 (P = 0.012) mutation and P = 0.043) and OS (HR = 1.998, P = 0.034). Mutations in fewer IDH1 (P = 0.012) mutation. No significant differ - TP53 (HR = 6.028, P = 0.001) and RUNX1 (HR = 6.028, ences were observed in mutation frequencies of NPM1, P = 0.001) were unfavorable for OS (Table  3). The mul - DNMT3A, RUNX1, MLL-PTD, IDH1, IDH2, and TP53 tivariate analysis indicated that FLT3-ITD (HR = 2.549, between the two groups (Table  1). These data suggest P = 0.006), TP53 (HR = 5.841, P = 0.002), and RUNX1 that the prognostic role of miR-425 expression may be (HR = 3.007, P = 0.007) mutational status remained to be independently associated with these gene mutations. an independent prognostic factor for OS (Table 3). How- In the allo-HSCT group, no significant differences were ever, no notable differences in survival were reported found in terms of age, gender, white blood cell count, BM between high- and low-miR-425-expression groups. Yang et al. J Transl Med (2018) 16:267 Page 4 of 11 Table 1 Comparison of clinical and molecular characteristics with miR-425 expression in AML patients Characteristic Chemotherapy group Allo‑HSCT group High miR‑425 Low miR‑425 P High miR‑425 Low miR‑425 P (n = 45) (n = 45) (n = 36) (n = 36) Age/years, median (range) 63 (22–88) 68 (33–83) 0.138 52 (25–72) 50 (18–69) 0.450 Age group/no. (%), years 0.652 0.793 < 60 16 (35.6) 13 (28.9) 27 (75.0) 25 (69.4) ≥ 60 29 (64.4) 32 (71.1) 9 (25.0) 11 (30.6) Gender/no. (%) 0.289 1.000 Male 28 (62.2) 22 (48.9) 21 (58.3) 20 (55.6) Female 17 (37.8) 23 (51.1) 15 (41.7) 16 (44.4) WBC/× 10 /L, median (range) 15.2 (0.7–298.4) 16.9 (1.0–297.4) 0.589 30.3 (1.5–98.8) 28.3 (0.6–223.8) 0.978 BM blast/ %, median (range) 67 (30–98) 75 (37–99) 0.050 68 (30–97) 76 (35–100) 0.131 PB blast/%, median (range) 18 (0–71) 53 (0–98) 0.002 41 (0–85) 53 (0–96) 0.116 FAB subtypes/no. (%) M0 0 (0.0) 8 (17.8) 0.006 3 (8.3) 6 (16.7) 0.478 M1 7 (15.6) 13 (28.9) 0.201 8 (22.2) 15 (41.7) 0.129 M2 13 (28.9) 8 (17.8) 0.231 13 (36.1) 6 (16.7) 0.107 M4 14 (31.1) 10 (22.2) 0.340 8 (22.2) 6 (16.7) 0.767 M5 9 (20) 4 (8.9) 0.230 3 (8.3) 1 (2.8) 0.614 M6 0 (0.0) 1 (2.2) 1.000 1 (2.8) 0 (0.0) 1.000 M7 1 (2.2) 1 (2.2) 1.000 0 (0.0) 1 (2.8) 1.000 Others 1 (2.2) 0 (0.0) 1.000 0 (0.0) 1 (2.8) 1.000 Karyotype/no. (%) Normal 21 (46.7) 23 (51.1) 0.833 17 (47.2) 17 (47.2) 1.000 Complex 5 (11.1) 7 (15.6) 0.758 5 (13.9) 7 (19.4) 0.753 MLL rearranged 2 (4.4) 1 (2.2) 1.000 2 (5.6) 1 (2.8) 1.000 CBFβ-MYH11 7 (15.6) 0 (0.0) 0.012 5 (13.9) 0 (0.0) 0.054 BCR-ABL1 1 (2.2) 0 (0.0) 1.000 1 (2.8) 1 (2.8) 1.000 RUNX1-RUNX1T 5 (11.1) 1 (2.2) 0.203 0 (0.0) 1 (2.8) 1.000 Others 4 (8.9) 13 (28.9) 0.029 6 (16.7) 9 (25) 0.563 Risk (cyto)/no. (%) Good 12 (26.7) 1 (2.2) 0.002 5 (13.9) 1 (2.8) 0.199 Intermediate 20 (44.4) 30 (66.7) 0.056 17 (47.2) 24 (66.7) 0.153 Poor 13 (28.9) 12 (26.7) 1.000 13 (36.1) 11 (30.6) 0.803 Others 0 (0.0) 2 (4.4) 0.494 1 (2.8) 0 (0.0) 1.000 FLT3-ITD/no. (%) 1.000 0.396 Presence 8 (17.8) 8 (17.8) 6 (16.7) 10 (27.8) Absence 37 (82.2) 37 (82.2) 30 (83.3) 26 (72.2) NPM1/no. (%) 0.367 0.430 Presence 12 (26.7) 17 (37.8) 8 (22.2) 12 (33.3) Absence 33 (73.3) 28 (62.2) 28 (77.8) 24 (66.7) DNMT3A/no. (%) 0.059 0.415 Presence 8 (17.8) 17 (37.8) 7 (19.4) 11 (30.6) Absence 37 (82.2) 28 (62.2) 29 (80.6) 25 (69.4) RUNX1/no. (%) 0.058 1.000 Presence 1 (2.2) 7 (15.6) 4 (11.1) 4 (11.1) Absence 44 (97.8) 38 (84.4) 32 (88.9) 32 (88.9) MLL-PTD/no. (%) 1.000 0.115 Presence 2 (4.4) 3 (6.7) 4 (11.1) 0 (0.0) Absence 43 (95.6) 42 (93.3) 32 (88.9) 36 (100.0) Yang et al. J Transl Med (2018) 16:267 Page 5 of 11 Table 1 (continued) Characteristic Chemotherapy group Allo‑HSCT group High miR‑425 Low miR‑425 P High miR‑425 Low miR‑425 P (n = 45) (n = 45) (n = 36) (n = 36) TP53/no. (%) 1.000 1.000 Mutation 5 (11.1) 5 (11.1) 2 (5.6) 2 (5.6) Wild type 40 (88.9) 40 (88.9) 34 (94.4) 34 (94.4) CEBPA/no. (%) 1.000 1.000 Mutation 2 (4.4) 1 (2.2) 4 (11.1) 4 (11.1) Wild type 43 (95.6) 44 (97.8) 32 (89.9) 32 (88.9) IDH1/no. (%) 0.012012 0.514 Mutation 0 (0.0) 7 (15.6) 4 (11.1) 7 (19.4) Wild type 45 (100.0) 38 (84.4) 32 (88.9) 29 (80.6) IDH2/no. (%) 1.000 0.710 Mutation 4 (8.9) 5 (11.1) 3 (8.3) 5 (13.9) Wild type 41 (91.1) 40 (88.9) 33 (91.7) 31 (86.1) WBC white blood cell, BM bone marrow, PB peripheral blood, FAB French–American–British classification, MLL mixed-lineage leukemia, FLT3-ITD internal tandem duplication of the FLT3 gene, NPM1 nucleophosmin, DNMT3A DNA methyltransferase 3A, RUNX1 runt related transcription factor 1, MLL-PTD partial tandem duplication of the MLL gene, CEBPA CCAAT/enhancerbinding protein α, IDH isocitrate dehydrogenase The median expression level of miR-425 was used to define high- and low-miR-425-expression groups. P values for continuous variables are from Mann–Whitney test; P values for categorical variables are from Chi square tests. The values represent frequencies (%). Complex karyotype is defined as more than or equal to 3 chromosomal abnormalities. The patients were divided into three risk groups (good, intermediate and poor) according to the cytogenetic risk classification Fig. 1 Kaplan–Meier survival curves of patients with respect to miR-425 expression. a, b Patients with high miR-425 expression had significantly longer OS and EFS in the chemotherapy group (n = 90). c, d Eec ff t of miR-425 expression on OS and EFS in patients undergoing allo-HSCT (n = 72) Yang et al. J Transl Med (2018) 16:267 Page 6 of 11 Table 2 Univariate and multivariate analyses in patients treated with chemotherapy Variables EFS OS HR (95% CI) P‑ value HR (95% CI) P‑ value Univariate analyses MiR-425 (high vs. low) 0.449 (0.279–0.721) 0.001 0.506 (0.316–0.811) 0.005 WBC (≥ 20 vs. < 20 × 10 /L) 0.939 (0.594–1.484) 0.786 0.936 (0.591–1.484) 0.779 FLT3-ITD (positive vs. negative) 1.242 (0.693–2.224) 0.467 1.192 (0.665–2.136) 0.555 NPM1 (mutated vs. wild) 1.168 (0.721–1.893) 0.527 1.044 (0.640–1.704) 0.862 DNMT3A (mutated vs. wild) 1.491 (0.909–2.446) 0.114 1.432 (0.868–2.362) 0.160 RUNX1 (mutated vs. wild) 1.464 (0.700–3.064) 0.312 1.591 (0.759–3.335) 0.219 TP53 (mutated vs. wild) 2.949 (1.510–7.561) 0.002 2.898 (1.487–5.694) 0.002 CEBPA (mutated vs. wild) 2.963 (0.910–9.648) 0.071 2.901 (0.892–9.434) 0.077 IDHI/IDH2 (mutated vs. wild) 1.006 (0.570–1.775) 0.983 0.954 (0.532–1.710) 0.874 NRAS/KRAS (mutated vs. wild) 1.143 (0.601–2.172) 0.684 1.188 (0.625–2.260) 0.599 MLL-PTD (mutated vs. wild) 0.836 (0.305–2.291) 0.727 0.910 (0.332–2.495) 0.855 Multivariate analyses MiR-425 (high vs. low) 0.432 (0.266–0.703) 0.001 0.502 (0.311–0.811) 0.005 FLT3-ITD (positive vs. negative) 1.582 (0.868–2.883) 0.134 – – TP53 (mutated vs. wild) 2.737 (1.377–5.438) 0.004 2.519 (1.286–4.933) 0.007 CEBPA (mutated vs. wild) 3.746 (1.102–12.736) 0.034 3.228 (0.959–10.864) 0.058 EFS event-free survival, OS overall survival, HR hazard ratio, CI confidence interval, WBC white blood cell, FLT3-ITD internal tandem duplication of the FLT3 gene, NPM1 nucleophosmin, DNMT3A DNA methyltransferase 3A, RUNX1 runt related transcription factor 1, MLL-PTD partial tandem duplication of the MLL gene, CEBPA CCAAT/ enhancerbinding protein α, IDH isocitrate dehydrogenase Cox proportional hazards model was used for EFS and OS. HRs greater than 1.0 indicate higher and those less than 1.0 indicate lower risk for EFS or OS Table 3 Univariate and multivariate analyses in patients treated with allo-HSCT Variables EFS OS HR (95% CI) P‑ value HR (95% CI) P‑ value Univariate analyses MiR-425 (high vs. low) 1.037 (0.624–1.724) 0.888 1.073 (0.626–1.840) 0.798 WBC (≥ 20 vs. < 20 × 10 /L) 1.530 (0.910–2.571) 0.108 0.949 (0.554–1.628) 0.851 FLT3-ITD (positive vs. negative) 1.873 (1.020–3.437) 0.043 1.998 (1.053–3.788) 0.034 NPM1 (mutated vs. wild) 0.913 (0.515–1.619) 0.755 0.879 (0.478–1.671) 0.678 DNMT3A (mutated vs. wild) 1.106 (0.615–1.989) 0.737 1.269 (0.686–2.347) 0.447 RUNX1 (mutated vs. wild) 1.375 (0.650–2.907) 0.404 2.253 (1.046–4.849) 0.038 TP53 (mutated vs. wild) 1.579 (0.565–4.411) 0.383 3.788 (1.289–11.133) 0.015 CEBPA (mutated vs. wild) 0.853 (0.366–1.989) 0.713 0.644 (0.256–1.620) 0.350 IDHI/IDH2 (mutated vs. wild) 0.761 (0.417–1.389) 0.374 0.802 (0.422–1.524) 0.500 NRAS/KRA S (mutated vs. wild) 1.373 (0.622–3.034) 0.433 0.658 (0.261–1.657) 0.374 MLL-PTD (mutated vs. wild) 6.093 (2.051–18.098) 0.001 3.106 (1.104–8.741) 0.032 Multivariate analyses WBC (≥ 20 vs. < 20 × 10 /L) 1.691 (0.973–2.940) 0.062 – – FLT3-ITD (positive vs. negative) 1.740 (0.934–3.239) 0.081 2.549 (1.306–4.975) 0.006 TP53 (mutated vs. wild) 2.657 (0.877–8.048) 0.084 5.841 (1.895–18.009) 0.002 RUNX1 (mutated vs. wild) – – 3.007 (1.355–6.673) 0.007 MLL-PTD (mutated vs. wild) 6.028 (2.001–18.158) 0.001 – – EFS event-free survival, OS overall survival, HR hazard ratio, CI confidence interval, WBC white blood cell, FLT3-ITD internal tandem duplication of the FLT3 gene, NPM1 nucleophosmin, DNMT3A DNA methyltransferase 3A, RUNX1 runt related transcription factor 1, MLL-PTD partial tandem duplication of the MLL gene, CEBPA CCAAT/ enhancerbinding protein α, IDH isocitrate dehydrogenase Cox proportional hazards model was used for EFS and OS. HRs greater than 1.0 indicate higher and those less than 1.0 indicate lower risk for EFS or OS Yang et al. J Transl Med (2018) 16:267 Page 7 of 11 Patients with low expression of miR‑425 benefited Biologic Insights from allo‑HSCT treatment To gain insights into the biological function of miR-425, All 162 patients were divided into two groups based gene/microRNA expression signatures were derived on the median expression levels of miR-425 to inves- using Spearman correlation analysis. We observed that tigate whether allo-HSCT could overcome the adverse the mRNA expression of 166 genes significantly corre - outcome of low miR-425 expression. In the low-miR- lated (P < 0.001) with that of miR-425. Of these genes, 102 425-expression group, the patients undergoing allo- correlated negatively and 64 correlated positively (Fig. 3). HSCT had significantly better OS (HR = 0.302, 95% MiR-425 expression negatively correlated with the lev- CI = 0.129–0.375, P < 0.0001) and EFS (HR = 0.379, els of the CD47, SMAD2, SMAD5, MAP4K3, MAP3K5, 95% CI = 0.192–0.523, P < 0.0001) compared with MAPK8, MLLT11, MIS2, and zinc finger protein fam - patients treated with chemotherapy (Fig.  2c, d). In the ily genes. Interestingly, MAP3K5, SMAD2, and SMAD5 high-miR-363-expression group, no significant dif- were in silico predicted targets of miR-425. Also, a nega- ferences in OS (P = 0.127) and EFS (P = 0.226) were tive correlation of miR-425 with the expression of IRF8 observed between chemotherapy and allo-HSCT treat- and KLF4 was found. Furthermore, the Gene Ontology ment types (Fig. 2a, b). analysis revealed that the genes involved in biologic pro- cesses, including cellular metabolism, macromolecule metabolism, RNA metabolism, cellular biosynthesis, Fig. 2 Allo-HSCT overcame the adverse prognosis of low miR-425 expression in AML. a, b A total of 162 patients were divided into two groups based on the median expression levels of miR-425. Kaplan–Meier survival curves of patients with respect to chemotherapy (n = 40) and allo-HSCT (n = 41) treatment in the low-miR-425-expression group. c, d Kaplan–Meier survival curves of patients with respect to chemotherapy (n = 50) and allo-HSCT (n = 31) treatment in the high-miR-425-expression group Yang et al. J Transl Med (2018) 16:267 Page 8 of 11 Fig. 3 Heat map of gene expression profile associated with miR-425 expression in patients with AML. Patients (columns) are ordered from left to right by increasing miR-425 expression levels. Genes (rows) are ordered by the hierarchical cluster analysis. Green color indicates expression levels lower than the median value for the given gene set, and red color indicates expression levels higher than the median value for the given gene set. The miR-425-correlated genes mentioned in the text are indicated embryo development, cell division, and protein phospho- patients with AML treated with chemotherapy. However, rylation, were significantly over-represented among the allo-HSCT could remarkably overcome the adverse effect differentially expressed genes correlated with miR-425 of low miR-425 expression. Thus, miR-425 might be con - expression (Table 4). sidered as a predictive molecular marker to guide the treatment choice between allo-HSCT and chemotherapy. Discussion Effective prognostic markers to guide the selection of Identification of novel predictive markers to guide clini - appropriate therapy for patients with AML are lacking. cal therapy for patients with AML is currently of spe- In the present study, the high miR-425 expression could cial interest. This study reported that miR-425 served predict the favorable outcome when other molecular as an independent prognostic factor in patients with prognostic markers were considered in multivariable AML. Furthermore, the results suggested that low miR- models. Thus, miR-425 might add to the prognostic effect 425 expression correlated with an adverse outcome in of different previously established molecular markers in a Yang et al. J Transl Med (2018) 16:267 Page 9 of 11 Table 4 Gene ontology terms of biological processes in the miR-425 associated expression profile GO ID GO terms Percentage of Members of the GO Term P‑ value Present in the miR‑425 Profile GO:0008152 Metabolic process 62.8 0.004 GO:0044237 Cellular metabolic process 59.6 0.002 GO:0043170 Macromolecule metabolic process 55.7 < 0.001 GO:0044267 Cellular protein metabolic process 30.7 0.029 GO:0031326 Regulation of cellular biosynthetic process 29.4 0.006 GO:0009889 Regulation of biosynthetic process 29.4 0.008 GO:0010468 Regulation of gene expression 29.4 0.009 GO:0051252 Regulation of RNA metabolic process 25.0 0.026 GO:0065009 Regulation of molecular function 20.5 0.019 GO:0006468 Protein phosphorylation 15.3 0.011 GO:0009790 Embryo development 8.9 0.026 GO:0051301 Cell division 7.7 0.004 GO:0032101 Regulation of response to external stimulus 7.7 0.019 GO:0010608 Posttranscriptional regulation of gene expression 5.8 0.025 GO:0042787 Protein ubiquitination 3.8 0.026 GO gene ontology highly mixed population of AML. These results provided targeting the IGF1 [15]. This function of miR-425 might an opportunity for potential therapeutic intervention contribute to the better response to chemotherapy in with synthetic miR-425 compounds. More importantly, patients with AML having high miR-425 expression. this study found that patients with low miR-425 expres- The activity of miR-425 has been recently characterized sion undergoing allo-HSCT had significantly better OS in solid tumors. Elevated miR-425 has been observed in and EFS compared with patients treated with chemother- gastric cancer, where it promotes cell proliferation and apy. Among the patients with high miR-425 expression, inhibits apoptosis by targeting PTEN [16]. A later study no benefit was reported for the allo-HSCT group com - revealed that miR-425 was also involved in gastric can- pared with the chemotherapy group. These finding sug - cer progression and metastasis by suppressing CYLD gested that patients with high miR-425 expression might [17]. In breast cancer, miR-425 promoted cell prolif- not benefit from allo-HSCT as the first-line treatment. eration through suppressing EGR1 [18]. Lower miR-425 u Th s, the expression of miR-425 might be useful for iden - limited the migration and invasion ability of esophageal tifying patients in need of strategies to choose the better squamous cell carcinoma [19]. MiR-425 has been found treatment types between chemotherapy and allo-HSCT. to be capable of inhibiting melanoma metastasis through Patients with low miR-425 expression may warrant the repressing the PI3  K-Akt pathway by targeting IGF-1 in strong consideration of early allo-HSCT. melanoma [15]. However, relatively little is known about Allo-HSCT has been confirmed to improve the prog - the biological role of miR-425 in AML. nosis of AML with gene mutations. TP53 is an inacti- The genes significantly correlated with miR-425 expres - vated tumor suppressor gene. The mutations of TP53 are sion were identified to further understand how miR-425 often observed in advanced- or complex-karyotype AML. expression affected the response to treatment and clini - However, a previous study showed that even after allo- cal outcome of patients with AML. The Gene Ontology geneic HSCT, patients harboring mutated p53 showed a analysis revealed that the genes involved in metabolic dismal result [12]. The analysis results also suggested that processes significantly correlated with miR-425 expres - mutations in TP53 were associated with a poor outcome sion. The dysregulated cellular metabolism is now widely even after allo-HSCT. The TP53 mutation was reported accepted as an emerging hallmark of AML. The aber - to induce drug resistance, eventually contributing to rant metabolism is crucial in leukemogenesis and chem- treatment failure [13]. TP53 is regulated by the PI3 K-Akt oresistance with the power to control both genetic and pathway. Therefore, blocking the activity of PI3  K-Akt epigenetic events in AML [20]. Furthermore, the miR- pathway might increase p53 activity, eventually increas- 425 level was found to be negatively correlated with the ing chemosensitivity [14]. A recent study demonstrated expression of leukemogenic genes, including CD47, that miR-425 further inhibited the PI3K-Akt pathway via SMAD2, SMAD5, MAP4K3, MAP3K5, MAPK8, and Yang et al. J Transl Med (2018) 16:267 Page 10 of 11 MLLT11. Available evidence proves that CD47 help leu- help improve the risk stratification and decision making kemia cells to avoid phagocytosis [21–23]. MAP4K3, as regarding the treatment of patients with AML. Further- direct LATS1/2-activating kinase, contributes to core more, allo-HSCT might overcome the adverse outcome components of the Hippo pathway [24] and participates associated with the low expression of miR-425 in AML. in amino acid signaling [25]. MAP3K5, as an apoptosis u Th s, the expression of miR-425 might be useful for iden - signal-related kinase, may be inactivated by Akt [26]. A tifying patients in need of strategies to choose better thera- previous study revealed the role of MAPK8 in controlling pies between chemotherapy and allo-HSCT. autophagy [27]. MLLT11, as an MLL fusion partner, has shown poor survival benefits in leukemias [28]. SMAD2, Abbreviations as a TGFƁ receptor–associated signaling molecule, is AML: acute myeloid leukemia; allo-HSCT: allogeneic hematopoietic stem cell involved in TGFB-induced growth arrest [29]. It is also transplantation; EFS: event-free survival; OS: overall survival; WBC: white blood cell; BM: bone marrow; PB: peripheral blood; FAB: French–American–British crucial in the chemoresistance of leukemic cells caused classification; MLL: mixed-lineage leukemia; FLT3-ITD: internal tandem duplica- by hypoxia [30, 31]. High expression of SMAD5 has been tion of the FLT3 gene; NPM1: nucleophosmin; DNMT3A: DNA methyltrans- found to be associated with the proliferation and dif- ferase 3A; RUNX1: runt related transcription factor 1; MLL-PTD: partial tandem duplication of the MLL gene; CEBPA: CCAAT/enhancerbinding protein α; IDH: ferentiation of osteoblasts in regulating leukemia [32]. isocitrate dehydrogenase. Notably, MAP3K5, SMAD2, and SMAD5 were predicted to be the targets of miR-425. Furthermore, a positive cor- Authors’ contributions CY, MN and XK designed the study and wrote the manuscript. TS, HZ, XS and relation of miR-425 expression with IRF8 and KLF4 was NZ performed statistical analyses. XL, YY, LX, SZ, JC, HC, ZY and ZL analyzed the found. IRF8 showed an inverse correlation with WT1, data. All authors read and approved the final manuscript. which had a worse effect on recurrence-free survival and Author details OS [33]. Increasing evidence links KLF4 to myeloid leu- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. kemias [34]. It exerts a powerful anti-leukemic effect by 2 Department of Hematology, Affiliated Hospital of Xuzhou Medical University, regulating microRNA and gene targets [35], suggesting Xuzhou, Jiangsu, China. Insititute of Nervous System Diseases, Xuzhou Medi- cal University, Xuzhou, Jiangsu, China. School of Physical Science and Tech- that KLF4 functions as a tumor suppressor in leukemia. nology, ShanghaiTech University, Shanghai, China. School of Life Science & Taken together, the miR-425-associated gene expression Medicine, Dalian University of Technology, Panjin, China. profiling analyses provided insights into the leukemo - Acknowledgements genic role of genes that are either direct or indirect tar- The authors thank The Cancer Genome Atlas Network. gets of miR-425. These miR-425-associated genes might support the clinical observation of AML defined by miR- Competing interests The authors declare that they have no competing interests. 425 expression. Our analysis was based on information obtained Availability of data and materials from The Cancer Genome Atlas (TCGA) database. The The datasets of this article were generated by TCGA dataset. strengths of the trial included its well-defined eligibil - Consent for publication ity criteria and uniform treatment regimens in accord- Not applicable. ance with NCCN guidelines. Furthermore, the study was Ethics approval and consent to participate designed and powered to detect > 99% of mutations that Written informed consent was obtained from all patients, and was approved are present in at least 5% of all de novo AML cases; cases by the human studies committee at Washington University. were chosen from a collection of more than 400 con- Funding sented AML samples to represent the currently recog- The research was supported by National Natural Science Foundation of nized subtypes of the disease (based on morphologic and China (81670142, 81772658, 81700199, 81500097); Jiangsu Provincial Key cytogenetic criteria). However, the data also presented Research and Development Program (BE2017636, BE2017638, BE2015625); The Foundation of Jiangsu Province Six Talents Peak (2016-WSN-136); Jiangsu some key limitations for analysis. Our analysis is a retro- Qing Lan Project for Mingshan Niu; Natural Science Foundation of Jiangsu spective design. It is restricted to available data and their Province (BK20180104, BK20141138); Xuzhou Key Research and Application inherent limitations. The small sample size may reduce of Basic Research Projects (KC17158); Postdoctoral Science Foundation of Jiangsu Province (1601096B); Colleges’ Science Foundation of Jiangsu Province the accuracy of our results. Therefore, the present results (16KJB320013, 15KJB320016). need to be verified in larger cohorts. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- Conclusions lished maps and institutional affiliations. The expression of miR-425 was independently associated with the clinical outcome in a highly heterogeneous popu- Received: 21 August 2018 Accepted: 26 September 2018 lation of AML. The expression analysis of miR-425 might Yang et al. J Transl Med (2018) 16:267 Page 11 of 11 References tumorigenicity of breast cancer cells depending on estrogen receptor 1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J status. PLoS Genet. 2013;9:e1003311. Med. 2015;373:1136–52. 19. Liu L, Zhao Z, Zhou W, Fan X, Zhan Q, Song Y. Enhanced expression of 2. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, miR-425 promotes esophageal squamous cell carcinoma tumorigenesis et al. Diagnosis and management of acute myeloid leukemia in adults: by targeting SMAD2. J Genet Genomics. 2015;42:601–11. recommendations from an international expert panel, on behalf of the 20. Abdel-Wahab O, Levine RL. Metabolism and the leukemic stem cell. J Exp European LeukemiaNet. Blood. 2010;115:453–74. Med. 2010;207:677–80. 3. Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, et al. Hematopoi- 21. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 etic stem-cell transplantation for acute leukemia in relapse or primary is upregulated on circulating hematopoietic stem cells and leukemia cells induction failure. J Clin Oncol. 2010;28:3730–8. to avoid phagocytosis. Cell. 2009;138:271–85. 4. Gregory TK, Wald D, Chen Y, Vermaat JM, Xiong Y, Tse W. Molecular prog- 22. Fu W, Li J, Zhang W, Li P. High expression of CD47 predicts adverse nostic markers for adult acute myeloid leukemia with normal cytogenet- prognosis in Chinese patients and suppresses immune response in ics. J Hematol Oncol. 2009;2:23. melanoma. Biomed Pharmacother. 2017;93:1190–6. 5. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, 23. Kong F, Gao F, Li H, Liu H, Zhang Y, Zheng R, et al. CD47: a potential et al. Diagnosis and management of AML in adults: 2017 ELN recommen- immunotherapy target for eliminating cancer cells. Clin Transl Oncol. dations from an international expert panel. Blood. 2017;129:424–47. 2016;18:1051–5. 6. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute 24. Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG, Hong AW, myeloid leukemia. J Clin Oncol. 2011;29:487–94. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 7. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid in the Hippo pathway. Nat Commun. 2015;6:8357. leukemia. Blood. 2005;106:1154–63. 25. Kim J, Guan KL. Amino acid signaling in TOR activation. Annu Rev Bio- 8. Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol chem. 2011;80:1001–32. Cell Biol. 2009;10:116–25. 26. Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecu- 9. Schwind S, Maharry K, Radmacher MD, Mrozek K, Holland KB, Margeson lar insights and advances in drug development. Br J Clin Pharmacol. D, et al. Prognostic significance of expression of a single microRNA, miR- 2016;82:943–56. 181a, in cytogenetically normal acute myeloid leukemia: a Cancer and 27. Hsu CL, Lee EX, Gordon KL, Paz EA, Shen WC, Ohnishi K, et al. MAP4K3 Leukemia Group B study. J Clin Oncol. 2010;28:5257–64. mediates amino acid-dependent regulation of autophagy via phospho- 10. Sun SM, Rockova V, Bullinger L, Dijkstra MK, Dohner H, Lowenberg B, et al. rylation of TFEB. Nat Commun. 2018;9:942. The prognostic relevance of miR-212 expression with survival in cytoge- 28. Xiong Y, Li Z, Ji M, Tan AC, Bemis J, Tse JV, et al. MIR29B regulates expres- netically and molecularly heterogeneous AML. Leukemia. 2013;27:100–6. sion of MLLT11 (AF1Q), an MLL fusion partner, and low MIR29B expression 11. Eisfeld AK, Marcucci G, Maharry K, Schwind S, Radmacher MD, Nicolet D, associates with adverse cytogenetics and poor overall survival in AML. Br et al. miR-3151 interplays with its host gene BAALC and independently J Haematol. 2011;153:753–7. affects outcome of patients with cytogenetically normal acute myeloid 29. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell mem- leukemia. Blood. 2012;120:249–58. brane to nucleus through SMAD proteins. Nature. 1997;390:465–71. 12. Middeke JM, Herold S, Rucker-Braun E, Berdel WE, Stelljes M, Kaufmann M, 30. Benito J, Shi Y, Szymanska B, Carol H, Boehm I, Lu H, et al. Pronounced et al. TP53 mutation in patients with high-risk acute myeloid leukaemia hypoxia in models of murine and human leukemia: high efficacy of treated with allogeneic haematopoietic stem cell transplantation. Br J hypoxia-activated prodrug PR-104. PLoS ONE. 2011;6:e23108. Haematol. 2016;172:914–22. 31. Zhang H, Akman HO, Smith EL, Zhao J, Murphy-Ullrich JE, Batuman OA. 13. Lai D, Visser-Grieve S, Yang X. Tumour suppressor genes in chemothera- Cellular response to hypoxia involves signaling via Smad proteins. Blood. peutic drug response. Biosci Rep. 2012;32:361–74. 2003;101:2253–60. 14. El-Deiry WS. The role of p53 in chemosensitivity and radiosensitivity. 32. Azizidoost S, Vijay V, Cogle CR, Khodadi E, Saki N. The role and clinical Oncogene. 2003;22:7486–95. implications of the endosteal niche and osteoblasts in regulating leuke- 15. Liu P, Hu Y, Ma L, Du M, Xia L, Hu Z. miR-425 inhibits melanoma metastasis mia. Clin Transl Oncol. 2017;19:1059–66. through repression of PI3 K-Akt pathway by targeting IGF-1. Biomed 33. Zhang Q, Zhang Q, Li Q, Liu B, Wang Y, Lin D, et al. Monitoring of WT1 Pharmacother. 2015;75:51–7. and its target gene IRF8 expression in acute myeloid leukemia and their 16. Ma J, Liu J, Wang Z, Gu X, Fan Y, Zhang W, et al. NF-kappaB-dependent significance. Int J Lab Hematol. 2015;37:e67–71. microRNA-425 upregulation promotes gastric cancer cell growth by 34. Kharas MG, Yusuf I, Scarfone VM, Yang VW, Segre JA, Huettner CS, et al. targeting PTEN upon IL-1beta induction. Mol Cancer. 2014;13:40. KLF4 suppresses transformation of pre-B cells by ABL oncogenes. Blood. 17. Yan YF, Gong FM, Wang BS, Zheng W. MiR-425-5p promotes tumor 2007;109:747–55. progression via modulation of CYLD in gastric cancer. Eur Rev Med Phar- 35. Morris VA, Cummings CL, Korb B, Boaglio S, Oehler VG. Deregulated KLF4 macol Sci. 2017;21:2130–6. expression in myeloid leukemias alters cell proliferation and differentia- 18. Di Leva G, Piovan C, Gasparini P, Ngankeu A, Taccioli C, Briskin D, et al. tion through MicroRNA and gene targets. Mol Cell Biol. 2016;36:559–73. Estrogen mediated-activation of miR-191/425 cluster modulates Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Translational Medicine Springer Journals

MiR-425 expression profiling in acute myeloid leukemia might guide the treatment choice between allogeneic transplantation and chemotherapy

Loading next page...
 
/lp/springer-journals/mir-425-expression-profiling-in-acute-myeloid-leukemia-might-guide-the-XH0nN58FfO

References (37)

Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Medicine/Public Health, general
eISSN
1479-5876
DOI
10.1186/s12967-018-1647-8
Publisher site
See Article on Publisher Site

Abstract

Background: Acute myeloid leukemia (AML) is a highly heterogeneous disease. MicroRNAs function as important biomarkers in the clinical prognosis of AML. Methods: This study identified miR-425 as a prognostic factor in AML by screening the TCGA dataset. A total of 162 patients with AML were enrolled for the study and divided into chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT ) groups. Results: In the chemotherapy group, patients with high miR-425 expression had significantly longer overall survival (OS) and event-free survival (EFS) compared with patients with low miR-425 expression. In multivariate analyses, high miR-425 expression remained independently predictive of a better OS (HR = 0.502, P = 0.005) and EFS (HR = 0.432, P = 0.001) compared with patients with low miR-425 expression. Then, all patients were divided into two groups based on the median expression levels of miR-425. Notably, the patients undergoing allo-HSCT had significantly bet - ter OS (HR = 0.302, P < 0.0001) and EFS (HR = 0.379, P < 0.0001) compared with patients treated with chemotherapy in the low-miR-425-expression group. Mechanistically, high miR-425 expression levels were associated with a profile significantly involved in regulating cellular metabolism. Among these genes, MAP3K5, SMAD2, and SMAD5 were predicted targets of miR-425. Conclusions: The expression of miR-425 may be useful in identifying patients in need of strategies to select the opti- mal therapy between chemotherapy and allo-HSCT treatment regimens. Patients with low miR-425 expression may consider early allo-HSCT. Keywords: miR-425, Acute myeloid leukemia, Prognosis, Chemotherapy, Allo-HSCT *Correspondence: msniu24@126.com; lihmd@163.com Chen Yang, Tingting Shao and Huihui Zhang contributed equally to this work Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. J Transl Med (2018) 16:267 Page 2 of 11 allo-HSCT and chemotherapy is largely unknown. There - Background fore, the predictive microRNAs for the early and accurate Acute myeloid leukemia (AML) originates from prolif- identification of optimal therapy in patients with AML erative, clonal, and occasionally poorly differentiated cells may help improve the clinical individual therapy. of the hematopoietic system [1]. AML is the most com- In this study, miR-425 was identified as a prognostic mon malignant myeloid disease in adults, accounting for factor in AML independent of other strong molecular 80% of adult leukemia [2]. Patients with AML showed predictors using genome-wide screening. A total of 162 heterogeneous outcomes after receiving different treat - patients newly diagnosed with AML were divided into ments, partly depending on patient age, karyotype, and two groups based on the allo-HSCT and chemotherapy mutational status. Conventional cytotoxic chemotherapy treatment types. The prognostic role of miR-425 was ana - is the first-line treatment option for patients with AML. lyzed in allo-HSCT and chemotherapy groups. A gene Allogeneic hematopoietic stem cell transplantation (allo- expression signature associated with miR-425 expression HSCT) offers strong anti-leukemic effect and potentially was derived in patients with AML to investigate biologic curative treatment in high-risk AML [3]. The progno - insights. sis of AML largely depends on treatment response and cytogenetic characteristics. Thus, the clinical and genetic prognostic markers are crucial in evaluating patients with AML and in guiding rational management. Methods Cytogenetics and molecular genetics were used for Patients stratifying patients with AML into favorable, intermedi- A total of 162 patients newly diagnosed with AML were ate, and adverse prognostic risk groups [4]. Prognostic recruited in this study. Seventy-two patients accepted stratification in cytogenetically normal AML was mainly allo-HSCT, and the remaining only accepted chemother- based on the mutational status of NPM1, FLT3, and apy (with 3  days of an anthracycline and 7  days of cyta- CEBPA [5]. Patients with FLT3-ITD, RUNX1, ASXL1, rabine). All data sets are publicly available in the TCGA and TP53 mutations were classified into the adverse risk database. According to the Declaration of Helsinki, all group [5]. The decision to perform allo-HSCT depended participants included in this study signed the written on the assessment of the risk–benefit ratio based on informed consent, and the study was approved by the cytogenetic and molecular genetic features. Patients with human studies committee of Washington University. The high-risk genetics were recommended to undergo allo- whole-genome and whole-exome sequencing analyses HSCT. However, patients with FLT3-ITD, TP53, and were performed to detect the mutational spectrum of WT1 mutations still had poor outcome and high relapse patients with AML. The mRNA and miRNA sequencing rate even after allo-HSCT as a post-remission therapy. were performed to analyze the expression of mRNAs and Currently, prognosis and optimal post-remission ther- miRNAs. All clinical, molecular and cytogenetic infor- apy cannot be predicted precisely in many subgroups of mation are publicly accessible from the TCGA website. patients with AML [6, 7]. Therefore, novel prognostic markers are urgently needed to identify which patients are best suited for chemotherapy and who should be Gene expression profiling offered allo-HSCT. Of the 162 patients, 155 had both microRNA and mRNA MicroRNAs play important roles in modulating cellu- expression data. These patient samples were used for lar behaviors by binding to the 3′-untranslated regions of identifying the gene expression profile associated with their target mRNAs. MicroRNAs regulate the expression miR-425 expression. For microRNA-seq data, read of intracellular proteins. They act as epigenetic regula - counts for each sample were normalized to reads per mil- tors and influence the self-renewal and differentiation of lion. For expression profiling, the expression values were leukemia stem cells [8]. Furthermore, the dysregulation logged (base 2) before analysis. A comparison of mRNA of microRNA expression has been shown to be associ- expression was made between patients with high and ated with the clinical outcome of patients with AML. low microRNA expression. Finally, gene rows were reor- MiR-181a has been confirmed to be associated with the dered using a hierarchical clustering analysis. The online favorable clinical outcome of patients with cytogeneti- applications miRBase Targets Version 7 and Targetscan cally normal AML [9]. High miR-212 expression is inde- Release 7.1 were used for the in silico target prediction of pendently predictive of favorable survival in AML [10]. microRNAs. The gene/microRNA expression signatures In contrast, high miR-3151 expression was identified as were derived by Spearman correlation analysis. Gene an unfavorable prognosticator for patients with AML ontology enrichment analysis of genes in miR-425-asso- [11]. However, the relevance of microRNAs as predictive ciated signature was conducted using the Database for molecular markers to guide the treatment choice between Annotation, Visualization, and Integrated Discovery. Yang et al. J Transl Med (2018) 16:267 Page 3 of 11 Definition of clinical endpoints and statistical analysis blast, PB blast, NPM1, DNMT3A, RUNX1, MLL-PTD, Overall survival (OS) was measured from the date of IDH1, IDH2, and TP53 between high- and low-miR-425 diagnosis to the date of death at the last follow-up. Event- expression groups. free survival (EFS) was measured from the date of diag- nosis to the date when the first adverse event, including Prognostic value of miR‑425 in patients relapse and death, occurred. Pearson Chi square and with chemotherapy and allo‑HSCT treatment Fisher’s exact tests were used for categorical variables. Kaplan–Meier curves and log-rank test were used to test The Mann–Whitney U test was performed for analyzing for differences in survival distribution so as to investigate continuous variables. Estimated distributions of OS and the prognostic role of miR-425 in patients with AML. In EFS were calculated using the Kaplan–Meier method, the chemotherapy group, the survival distribution curves and the log-rank test was used to compare differences showed that patients with high miR-425 expression had between survival curves. In univariate and multivariate significantly longer OS (P = 0.0024) and EFS (P = 0.0004) analyses, Cox proportional hazards models were used to compared with patients with low miR-425 expression test the relationship between survival and miR-425. The (Fig.  1a, b). However, no significant differences were hazard ratio (HR) and its 95% confidence interval (CI) found between high- and low-miR-425-expression were assessed using the Cox proportional hazards model. groups in patients undergoing allo-HSCT (Fig.  1c, d). All statistical tests were performed as two sided, and a P These data suggested that high expression of miR-425 value < 0.05 was considered statistically significant. SPSS specifically predicted a favorable outcome in patients software 18.0 and GraphPad Prism software 6.0 were with AML treated with chemotherapy. used for the statistical analysis in this study. MiR‑425 was independently associated with a clinical Results outcome in AML Associations of miR‑425 expression with clinical Univariate and multivariate analyses were performed and molecular features to assess the value of miR-425 in predicting the OS and Details on the molecular and clinical characteristics EFS of patients with AML. In the chemotherapy group, of the patients are summarized in Table  1. Pearson Chi the univariate analysis showed that the high expres- square test, Fisher’s exact test, and Mann–Whitney U sion of miR-425 had a prognostic value for predict- test were performed to investigate the associations of ing EFS (HR = 0.449, 95% CI = 0.279–0.721, P = 0.001) miR-425 with clinical and molecular characteristics. and OS (HR = 0.506, 95% CI = 0.316–0.811, P = 0.005). The median expression level of miR-425 was used to In the multivariate analysis, miR-425 and several well- define high- and low-miR-425-expression groups. In the known prognostic factors were included into the model chemotherapy group, patients with low miR-425 expres- (Table 2). High miR-425 remained independently predic- sion were more often diagnosed with M0 compared with tive of longer EFS (HR = 0.432, 95% CI = 0.266–0.703, patients with high miR-425 expression (P = 0.006). More- P = 0.001) after adjusting for TP53 (P = 0.004) and over, patients with higher miR-425 expression in the CEBPA (P = 0.034). High miR-425 expression was also chemotherapy group had a lower BM (P = 0.050) and PB independently predictive of longer OS (HR = 0.502, 95% blast (P = 0.002) counts. Patients with miR-425 upregu- CI = 0.311–0.811, P = 0.005) after adjusting for the P53 lation included more good risk cases (P = 0.002). AML mutational status (HR = 2.519, 95% CI = 1.286–4.933, is a complex disease, characterized by multiple somati- P = 0.007). cally acquired driver mutations. Genetic abnormali- In the allo-HSCT group, the univariate analysis ties are powerful prognostic factors for AML. Thus, we showed that patients with MLL-PTD had shorter EFS analyzed if miR-425 expression associated with the gene (HR = 6.028, P = 0.001) and OS (HR = 3.106, P = 0.032). mutation status. Patients with higher miR-425 expression FLT3-ITD was unfavorable for both EFS (HR = 1.873, often had more CBFβ-MYH11 (P = 0.012) mutation and P = 0.043) and OS (HR = 1.998, P = 0.034). Mutations in fewer IDH1 (P = 0.012) mutation. No significant differ - TP53 (HR = 6.028, P = 0.001) and RUNX1 (HR = 6.028, ences were observed in mutation frequencies of NPM1, P = 0.001) were unfavorable for OS (Table  3). The mul - DNMT3A, RUNX1, MLL-PTD, IDH1, IDH2, and TP53 tivariate analysis indicated that FLT3-ITD (HR = 2.549, between the two groups (Table  1). These data suggest P = 0.006), TP53 (HR = 5.841, P = 0.002), and RUNX1 that the prognostic role of miR-425 expression may be (HR = 3.007, P = 0.007) mutational status remained to be independently associated with these gene mutations. an independent prognostic factor for OS (Table 3). How- In the allo-HSCT group, no significant differences were ever, no notable differences in survival were reported found in terms of age, gender, white blood cell count, BM between high- and low-miR-425-expression groups. Yang et al. J Transl Med (2018) 16:267 Page 4 of 11 Table 1 Comparison of clinical and molecular characteristics with miR-425 expression in AML patients Characteristic Chemotherapy group Allo‑HSCT group High miR‑425 Low miR‑425 P High miR‑425 Low miR‑425 P (n = 45) (n = 45) (n = 36) (n = 36) Age/years, median (range) 63 (22–88) 68 (33–83) 0.138 52 (25–72) 50 (18–69) 0.450 Age group/no. (%), years 0.652 0.793 < 60 16 (35.6) 13 (28.9) 27 (75.0) 25 (69.4) ≥ 60 29 (64.4) 32 (71.1) 9 (25.0) 11 (30.6) Gender/no. (%) 0.289 1.000 Male 28 (62.2) 22 (48.9) 21 (58.3) 20 (55.6) Female 17 (37.8) 23 (51.1) 15 (41.7) 16 (44.4) WBC/× 10 /L, median (range) 15.2 (0.7–298.4) 16.9 (1.0–297.4) 0.589 30.3 (1.5–98.8) 28.3 (0.6–223.8) 0.978 BM blast/ %, median (range) 67 (30–98) 75 (37–99) 0.050 68 (30–97) 76 (35–100) 0.131 PB blast/%, median (range) 18 (0–71) 53 (0–98) 0.002 41 (0–85) 53 (0–96) 0.116 FAB subtypes/no. (%) M0 0 (0.0) 8 (17.8) 0.006 3 (8.3) 6 (16.7) 0.478 M1 7 (15.6) 13 (28.9) 0.201 8 (22.2) 15 (41.7) 0.129 M2 13 (28.9) 8 (17.8) 0.231 13 (36.1) 6 (16.7) 0.107 M4 14 (31.1) 10 (22.2) 0.340 8 (22.2) 6 (16.7) 0.767 M5 9 (20) 4 (8.9) 0.230 3 (8.3) 1 (2.8) 0.614 M6 0 (0.0) 1 (2.2) 1.000 1 (2.8) 0 (0.0) 1.000 M7 1 (2.2) 1 (2.2) 1.000 0 (0.0) 1 (2.8) 1.000 Others 1 (2.2) 0 (0.0) 1.000 0 (0.0) 1 (2.8) 1.000 Karyotype/no. (%) Normal 21 (46.7) 23 (51.1) 0.833 17 (47.2) 17 (47.2) 1.000 Complex 5 (11.1) 7 (15.6) 0.758 5 (13.9) 7 (19.4) 0.753 MLL rearranged 2 (4.4) 1 (2.2) 1.000 2 (5.6) 1 (2.8) 1.000 CBFβ-MYH11 7 (15.6) 0 (0.0) 0.012 5 (13.9) 0 (0.0) 0.054 BCR-ABL1 1 (2.2) 0 (0.0) 1.000 1 (2.8) 1 (2.8) 1.000 RUNX1-RUNX1T 5 (11.1) 1 (2.2) 0.203 0 (0.0) 1 (2.8) 1.000 Others 4 (8.9) 13 (28.9) 0.029 6 (16.7) 9 (25) 0.563 Risk (cyto)/no. (%) Good 12 (26.7) 1 (2.2) 0.002 5 (13.9) 1 (2.8) 0.199 Intermediate 20 (44.4) 30 (66.7) 0.056 17 (47.2) 24 (66.7) 0.153 Poor 13 (28.9) 12 (26.7) 1.000 13 (36.1) 11 (30.6) 0.803 Others 0 (0.0) 2 (4.4) 0.494 1 (2.8) 0 (0.0) 1.000 FLT3-ITD/no. (%) 1.000 0.396 Presence 8 (17.8) 8 (17.8) 6 (16.7) 10 (27.8) Absence 37 (82.2) 37 (82.2) 30 (83.3) 26 (72.2) NPM1/no. (%) 0.367 0.430 Presence 12 (26.7) 17 (37.8) 8 (22.2) 12 (33.3) Absence 33 (73.3) 28 (62.2) 28 (77.8) 24 (66.7) DNMT3A/no. (%) 0.059 0.415 Presence 8 (17.8) 17 (37.8) 7 (19.4) 11 (30.6) Absence 37 (82.2) 28 (62.2) 29 (80.6) 25 (69.4) RUNX1/no. (%) 0.058 1.000 Presence 1 (2.2) 7 (15.6) 4 (11.1) 4 (11.1) Absence 44 (97.8) 38 (84.4) 32 (88.9) 32 (88.9) MLL-PTD/no. (%) 1.000 0.115 Presence 2 (4.4) 3 (6.7) 4 (11.1) 0 (0.0) Absence 43 (95.6) 42 (93.3) 32 (88.9) 36 (100.0) Yang et al. J Transl Med (2018) 16:267 Page 5 of 11 Table 1 (continued) Characteristic Chemotherapy group Allo‑HSCT group High miR‑425 Low miR‑425 P High miR‑425 Low miR‑425 P (n = 45) (n = 45) (n = 36) (n = 36) TP53/no. (%) 1.000 1.000 Mutation 5 (11.1) 5 (11.1) 2 (5.6) 2 (5.6) Wild type 40 (88.9) 40 (88.9) 34 (94.4) 34 (94.4) CEBPA/no. (%) 1.000 1.000 Mutation 2 (4.4) 1 (2.2) 4 (11.1) 4 (11.1) Wild type 43 (95.6) 44 (97.8) 32 (89.9) 32 (88.9) IDH1/no. (%) 0.012012 0.514 Mutation 0 (0.0) 7 (15.6) 4 (11.1) 7 (19.4) Wild type 45 (100.0) 38 (84.4) 32 (88.9) 29 (80.6) IDH2/no. (%) 1.000 0.710 Mutation 4 (8.9) 5 (11.1) 3 (8.3) 5 (13.9) Wild type 41 (91.1) 40 (88.9) 33 (91.7) 31 (86.1) WBC white blood cell, BM bone marrow, PB peripheral blood, FAB French–American–British classification, MLL mixed-lineage leukemia, FLT3-ITD internal tandem duplication of the FLT3 gene, NPM1 nucleophosmin, DNMT3A DNA methyltransferase 3A, RUNX1 runt related transcription factor 1, MLL-PTD partial tandem duplication of the MLL gene, CEBPA CCAAT/enhancerbinding protein α, IDH isocitrate dehydrogenase The median expression level of miR-425 was used to define high- and low-miR-425-expression groups. P values for continuous variables are from Mann–Whitney test; P values for categorical variables are from Chi square tests. The values represent frequencies (%). Complex karyotype is defined as more than or equal to 3 chromosomal abnormalities. The patients were divided into three risk groups (good, intermediate and poor) according to the cytogenetic risk classification Fig. 1 Kaplan–Meier survival curves of patients with respect to miR-425 expression. a, b Patients with high miR-425 expression had significantly longer OS and EFS in the chemotherapy group (n = 90). c, d Eec ff t of miR-425 expression on OS and EFS in patients undergoing allo-HSCT (n = 72) Yang et al. J Transl Med (2018) 16:267 Page 6 of 11 Table 2 Univariate and multivariate analyses in patients treated with chemotherapy Variables EFS OS HR (95% CI) P‑ value HR (95% CI) P‑ value Univariate analyses MiR-425 (high vs. low) 0.449 (0.279–0.721) 0.001 0.506 (0.316–0.811) 0.005 WBC (≥ 20 vs. < 20 × 10 /L) 0.939 (0.594–1.484) 0.786 0.936 (0.591–1.484) 0.779 FLT3-ITD (positive vs. negative) 1.242 (0.693–2.224) 0.467 1.192 (0.665–2.136) 0.555 NPM1 (mutated vs. wild) 1.168 (0.721–1.893) 0.527 1.044 (0.640–1.704) 0.862 DNMT3A (mutated vs. wild) 1.491 (0.909–2.446) 0.114 1.432 (0.868–2.362) 0.160 RUNX1 (mutated vs. wild) 1.464 (0.700–3.064) 0.312 1.591 (0.759–3.335) 0.219 TP53 (mutated vs. wild) 2.949 (1.510–7.561) 0.002 2.898 (1.487–5.694) 0.002 CEBPA (mutated vs. wild) 2.963 (0.910–9.648) 0.071 2.901 (0.892–9.434) 0.077 IDHI/IDH2 (mutated vs. wild) 1.006 (0.570–1.775) 0.983 0.954 (0.532–1.710) 0.874 NRAS/KRAS (mutated vs. wild) 1.143 (0.601–2.172) 0.684 1.188 (0.625–2.260) 0.599 MLL-PTD (mutated vs. wild) 0.836 (0.305–2.291) 0.727 0.910 (0.332–2.495) 0.855 Multivariate analyses MiR-425 (high vs. low) 0.432 (0.266–0.703) 0.001 0.502 (0.311–0.811) 0.005 FLT3-ITD (positive vs. negative) 1.582 (0.868–2.883) 0.134 – – TP53 (mutated vs. wild) 2.737 (1.377–5.438) 0.004 2.519 (1.286–4.933) 0.007 CEBPA (mutated vs. wild) 3.746 (1.102–12.736) 0.034 3.228 (0.959–10.864) 0.058 EFS event-free survival, OS overall survival, HR hazard ratio, CI confidence interval, WBC white blood cell, FLT3-ITD internal tandem duplication of the FLT3 gene, NPM1 nucleophosmin, DNMT3A DNA methyltransferase 3A, RUNX1 runt related transcription factor 1, MLL-PTD partial tandem duplication of the MLL gene, CEBPA CCAAT/ enhancerbinding protein α, IDH isocitrate dehydrogenase Cox proportional hazards model was used for EFS and OS. HRs greater than 1.0 indicate higher and those less than 1.0 indicate lower risk for EFS or OS Table 3 Univariate and multivariate analyses in patients treated with allo-HSCT Variables EFS OS HR (95% CI) P‑ value HR (95% CI) P‑ value Univariate analyses MiR-425 (high vs. low) 1.037 (0.624–1.724) 0.888 1.073 (0.626–1.840) 0.798 WBC (≥ 20 vs. < 20 × 10 /L) 1.530 (0.910–2.571) 0.108 0.949 (0.554–1.628) 0.851 FLT3-ITD (positive vs. negative) 1.873 (1.020–3.437) 0.043 1.998 (1.053–3.788) 0.034 NPM1 (mutated vs. wild) 0.913 (0.515–1.619) 0.755 0.879 (0.478–1.671) 0.678 DNMT3A (mutated vs. wild) 1.106 (0.615–1.989) 0.737 1.269 (0.686–2.347) 0.447 RUNX1 (mutated vs. wild) 1.375 (0.650–2.907) 0.404 2.253 (1.046–4.849) 0.038 TP53 (mutated vs. wild) 1.579 (0.565–4.411) 0.383 3.788 (1.289–11.133) 0.015 CEBPA (mutated vs. wild) 0.853 (0.366–1.989) 0.713 0.644 (0.256–1.620) 0.350 IDHI/IDH2 (mutated vs. wild) 0.761 (0.417–1.389) 0.374 0.802 (0.422–1.524) 0.500 NRAS/KRA S (mutated vs. wild) 1.373 (0.622–3.034) 0.433 0.658 (0.261–1.657) 0.374 MLL-PTD (mutated vs. wild) 6.093 (2.051–18.098) 0.001 3.106 (1.104–8.741) 0.032 Multivariate analyses WBC (≥ 20 vs. < 20 × 10 /L) 1.691 (0.973–2.940) 0.062 – – FLT3-ITD (positive vs. negative) 1.740 (0.934–3.239) 0.081 2.549 (1.306–4.975) 0.006 TP53 (mutated vs. wild) 2.657 (0.877–8.048) 0.084 5.841 (1.895–18.009) 0.002 RUNX1 (mutated vs. wild) – – 3.007 (1.355–6.673) 0.007 MLL-PTD (mutated vs. wild) 6.028 (2.001–18.158) 0.001 – – EFS event-free survival, OS overall survival, HR hazard ratio, CI confidence interval, WBC white blood cell, FLT3-ITD internal tandem duplication of the FLT3 gene, NPM1 nucleophosmin, DNMT3A DNA methyltransferase 3A, RUNX1 runt related transcription factor 1, MLL-PTD partial tandem duplication of the MLL gene, CEBPA CCAAT/ enhancerbinding protein α, IDH isocitrate dehydrogenase Cox proportional hazards model was used for EFS and OS. HRs greater than 1.0 indicate higher and those less than 1.0 indicate lower risk for EFS or OS Yang et al. J Transl Med (2018) 16:267 Page 7 of 11 Patients with low expression of miR‑425 benefited Biologic Insights from allo‑HSCT treatment To gain insights into the biological function of miR-425, All 162 patients were divided into two groups based gene/microRNA expression signatures were derived on the median expression levels of miR-425 to inves- using Spearman correlation analysis. We observed that tigate whether allo-HSCT could overcome the adverse the mRNA expression of 166 genes significantly corre - outcome of low miR-425 expression. In the low-miR- lated (P < 0.001) with that of miR-425. Of these genes, 102 425-expression group, the patients undergoing allo- correlated negatively and 64 correlated positively (Fig. 3). HSCT had significantly better OS (HR = 0.302, 95% MiR-425 expression negatively correlated with the lev- CI = 0.129–0.375, P < 0.0001) and EFS (HR = 0.379, els of the CD47, SMAD2, SMAD5, MAP4K3, MAP3K5, 95% CI = 0.192–0.523, P < 0.0001) compared with MAPK8, MLLT11, MIS2, and zinc finger protein fam - patients treated with chemotherapy (Fig.  2c, d). In the ily genes. Interestingly, MAP3K5, SMAD2, and SMAD5 high-miR-363-expression group, no significant dif- were in silico predicted targets of miR-425. Also, a nega- ferences in OS (P = 0.127) and EFS (P = 0.226) were tive correlation of miR-425 with the expression of IRF8 observed between chemotherapy and allo-HSCT treat- and KLF4 was found. Furthermore, the Gene Ontology ment types (Fig. 2a, b). analysis revealed that the genes involved in biologic pro- cesses, including cellular metabolism, macromolecule metabolism, RNA metabolism, cellular biosynthesis, Fig. 2 Allo-HSCT overcame the adverse prognosis of low miR-425 expression in AML. a, b A total of 162 patients were divided into two groups based on the median expression levels of miR-425. Kaplan–Meier survival curves of patients with respect to chemotherapy (n = 40) and allo-HSCT (n = 41) treatment in the low-miR-425-expression group. c, d Kaplan–Meier survival curves of patients with respect to chemotherapy (n = 50) and allo-HSCT (n = 31) treatment in the high-miR-425-expression group Yang et al. J Transl Med (2018) 16:267 Page 8 of 11 Fig. 3 Heat map of gene expression profile associated with miR-425 expression in patients with AML. Patients (columns) are ordered from left to right by increasing miR-425 expression levels. Genes (rows) are ordered by the hierarchical cluster analysis. Green color indicates expression levels lower than the median value for the given gene set, and red color indicates expression levels higher than the median value for the given gene set. The miR-425-correlated genes mentioned in the text are indicated embryo development, cell division, and protein phospho- patients with AML treated with chemotherapy. However, rylation, were significantly over-represented among the allo-HSCT could remarkably overcome the adverse effect differentially expressed genes correlated with miR-425 of low miR-425 expression. Thus, miR-425 might be con - expression (Table 4). sidered as a predictive molecular marker to guide the treatment choice between allo-HSCT and chemotherapy. Discussion Effective prognostic markers to guide the selection of Identification of novel predictive markers to guide clini - appropriate therapy for patients with AML are lacking. cal therapy for patients with AML is currently of spe- In the present study, the high miR-425 expression could cial interest. This study reported that miR-425 served predict the favorable outcome when other molecular as an independent prognostic factor in patients with prognostic markers were considered in multivariable AML. Furthermore, the results suggested that low miR- models. Thus, miR-425 might add to the prognostic effect 425 expression correlated with an adverse outcome in of different previously established molecular markers in a Yang et al. J Transl Med (2018) 16:267 Page 9 of 11 Table 4 Gene ontology terms of biological processes in the miR-425 associated expression profile GO ID GO terms Percentage of Members of the GO Term P‑ value Present in the miR‑425 Profile GO:0008152 Metabolic process 62.8 0.004 GO:0044237 Cellular metabolic process 59.6 0.002 GO:0043170 Macromolecule metabolic process 55.7 < 0.001 GO:0044267 Cellular protein metabolic process 30.7 0.029 GO:0031326 Regulation of cellular biosynthetic process 29.4 0.006 GO:0009889 Regulation of biosynthetic process 29.4 0.008 GO:0010468 Regulation of gene expression 29.4 0.009 GO:0051252 Regulation of RNA metabolic process 25.0 0.026 GO:0065009 Regulation of molecular function 20.5 0.019 GO:0006468 Protein phosphorylation 15.3 0.011 GO:0009790 Embryo development 8.9 0.026 GO:0051301 Cell division 7.7 0.004 GO:0032101 Regulation of response to external stimulus 7.7 0.019 GO:0010608 Posttranscriptional regulation of gene expression 5.8 0.025 GO:0042787 Protein ubiquitination 3.8 0.026 GO gene ontology highly mixed population of AML. These results provided targeting the IGF1 [15]. This function of miR-425 might an opportunity for potential therapeutic intervention contribute to the better response to chemotherapy in with synthetic miR-425 compounds. More importantly, patients with AML having high miR-425 expression. this study found that patients with low miR-425 expres- The activity of miR-425 has been recently characterized sion undergoing allo-HSCT had significantly better OS in solid tumors. Elevated miR-425 has been observed in and EFS compared with patients treated with chemother- gastric cancer, where it promotes cell proliferation and apy. Among the patients with high miR-425 expression, inhibits apoptosis by targeting PTEN [16]. A later study no benefit was reported for the allo-HSCT group com - revealed that miR-425 was also involved in gastric can- pared with the chemotherapy group. These finding sug - cer progression and metastasis by suppressing CYLD gested that patients with high miR-425 expression might [17]. In breast cancer, miR-425 promoted cell prolif- not benefit from allo-HSCT as the first-line treatment. eration through suppressing EGR1 [18]. Lower miR-425 u Th s, the expression of miR-425 might be useful for iden - limited the migration and invasion ability of esophageal tifying patients in need of strategies to choose the better squamous cell carcinoma [19]. MiR-425 has been found treatment types between chemotherapy and allo-HSCT. to be capable of inhibiting melanoma metastasis through Patients with low miR-425 expression may warrant the repressing the PI3  K-Akt pathway by targeting IGF-1 in strong consideration of early allo-HSCT. melanoma [15]. However, relatively little is known about Allo-HSCT has been confirmed to improve the prog - the biological role of miR-425 in AML. nosis of AML with gene mutations. TP53 is an inacti- The genes significantly correlated with miR-425 expres - vated tumor suppressor gene. The mutations of TP53 are sion were identified to further understand how miR-425 often observed in advanced- or complex-karyotype AML. expression affected the response to treatment and clini - However, a previous study showed that even after allo- cal outcome of patients with AML. The Gene Ontology geneic HSCT, patients harboring mutated p53 showed a analysis revealed that the genes involved in metabolic dismal result [12]. The analysis results also suggested that processes significantly correlated with miR-425 expres - mutations in TP53 were associated with a poor outcome sion. The dysregulated cellular metabolism is now widely even after allo-HSCT. The TP53 mutation was reported accepted as an emerging hallmark of AML. The aber - to induce drug resistance, eventually contributing to rant metabolism is crucial in leukemogenesis and chem- treatment failure [13]. TP53 is regulated by the PI3 K-Akt oresistance with the power to control both genetic and pathway. Therefore, blocking the activity of PI3  K-Akt epigenetic events in AML [20]. Furthermore, the miR- pathway might increase p53 activity, eventually increas- 425 level was found to be negatively correlated with the ing chemosensitivity [14]. A recent study demonstrated expression of leukemogenic genes, including CD47, that miR-425 further inhibited the PI3K-Akt pathway via SMAD2, SMAD5, MAP4K3, MAP3K5, MAPK8, and Yang et al. J Transl Med (2018) 16:267 Page 10 of 11 MLLT11. Available evidence proves that CD47 help leu- help improve the risk stratification and decision making kemia cells to avoid phagocytosis [21–23]. MAP4K3, as regarding the treatment of patients with AML. Further- direct LATS1/2-activating kinase, contributes to core more, allo-HSCT might overcome the adverse outcome components of the Hippo pathway [24] and participates associated with the low expression of miR-425 in AML. in amino acid signaling [25]. MAP3K5, as an apoptosis u Th s, the expression of miR-425 might be useful for iden - signal-related kinase, may be inactivated by Akt [26]. A tifying patients in need of strategies to choose better thera- previous study revealed the role of MAPK8 in controlling pies between chemotherapy and allo-HSCT. autophagy [27]. MLLT11, as an MLL fusion partner, has shown poor survival benefits in leukemias [28]. SMAD2, Abbreviations as a TGFƁ receptor–associated signaling molecule, is AML: acute myeloid leukemia; allo-HSCT: allogeneic hematopoietic stem cell involved in TGFB-induced growth arrest [29]. It is also transplantation; EFS: event-free survival; OS: overall survival; WBC: white blood cell; BM: bone marrow; PB: peripheral blood; FAB: French–American–British crucial in the chemoresistance of leukemic cells caused classification; MLL: mixed-lineage leukemia; FLT3-ITD: internal tandem duplica- by hypoxia [30, 31]. High expression of SMAD5 has been tion of the FLT3 gene; NPM1: nucleophosmin; DNMT3A: DNA methyltrans- found to be associated with the proliferation and dif- ferase 3A; RUNX1: runt related transcription factor 1; MLL-PTD: partial tandem duplication of the MLL gene; CEBPA: CCAAT/enhancerbinding protein α; IDH: ferentiation of osteoblasts in regulating leukemia [32]. isocitrate dehydrogenase. Notably, MAP3K5, SMAD2, and SMAD5 were predicted to be the targets of miR-425. Furthermore, a positive cor- Authors’ contributions CY, MN and XK designed the study and wrote the manuscript. TS, HZ, XS and relation of miR-425 expression with IRF8 and KLF4 was NZ performed statistical analyses. XL, YY, LX, SZ, JC, HC, ZY and ZL analyzed the found. IRF8 showed an inverse correlation with WT1, data. All authors read and approved the final manuscript. which had a worse effect on recurrence-free survival and Author details OS [33]. Increasing evidence links KLF4 to myeloid leu- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. kemias [34]. It exerts a powerful anti-leukemic effect by 2 Department of Hematology, Affiliated Hospital of Xuzhou Medical University, regulating microRNA and gene targets [35], suggesting Xuzhou, Jiangsu, China. Insititute of Nervous System Diseases, Xuzhou Medi- cal University, Xuzhou, Jiangsu, China. School of Physical Science and Tech- that KLF4 functions as a tumor suppressor in leukemia. nology, ShanghaiTech University, Shanghai, China. School of Life Science & Taken together, the miR-425-associated gene expression Medicine, Dalian University of Technology, Panjin, China. profiling analyses provided insights into the leukemo - Acknowledgements genic role of genes that are either direct or indirect tar- The authors thank The Cancer Genome Atlas Network. gets of miR-425. These miR-425-associated genes might support the clinical observation of AML defined by miR- Competing interests The authors declare that they have no competing interests. 425 expression. Our analysis was based on information obtained Availability of data and materials from The Cancer Genome Atlas (TCGA) database. The The datasets of this article were generated by TCGA dataset. strengths of the trial included its well-defined eligibil - Consent for publication ity criteria and uniform treatment regimens in accord- Not applicable. ance with NCCN guidelines. Furthermore, the study was Ethics approval and consent to participate designed and powered to detect > 99% of mutations that Written informed consent was obtained from all patients, and was approved are present in at least 5% of all de novo AML cases; cases by the human studies committee at Washington University. were chosen from a collection of more than 400 con- Funding sented AML samples to represent the currently recog- The research was supported by National Natural Science Foundation of nized subtypes of the disease (based on morphologic and China (81670142, 81772658, 81700199, 81500097); Jiangsu Provincial Key cytogenetic criteria). However, the data also presented Research and Development Program (BE2017636, BE2017638, BE2015625); The Foundation of Jiangsu Province Six Talents Peak (2016-WSN-136); Jiangsu some key limitations for analysis. Our analysis is a retro- Qing Lan Project for Mingshan Niu; Natural Science Foundation of Jiangsu spective design. It is restricted to available data and their Province (BK20180104, BK20141138); Xuzhou Key Research and Application inherent limitations. The small sample size may reduce of Basic Research Projects (KC17158); Postdoctoral Science Foundation of Jiangsu Province (1601096B); Colleges’ Science Foundation of Jiangsu Province the accuracy of our results. Therefore, the present results (16KJB320013, 15KJB320016). need to be verified in larger cohorts. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- Conclusions lished maps and institutional affiliations. The expression of miR-425 was independently associated with the clinical outcome in a highly heterogeneous popu- Received: 21 August 2018 Accepted: 26 September 2018 lation of AML. The expression analysis of miR-425 might Yang et al. J Transl Med (2018) 16:267 Page 11 of 11 References tumorigenicity of breast cancer cells depending on estrogen receptor 1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J status. PLoS Genet. 2013;9:e1003311. Med. 2015;373:1136–52. 19. Liu L, Zhao Z, Zhou W, Fan X, Zhan Q, Song Y. Enhanced expression of 2. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, miR-425 promotes esophageal squamous cell carcinoma tumorigenesis et al. Diagnosis and management of acute myeloid leukemia in adults: by targeting SMAD2. J Genet Genomics. 2015;42:601–11. recommendations from an international expert panel, on behalf of the 20. Abdel-Wahab O, Levine RL. Metabolism and the leukemic stem cell. J Exp European LeukemiaNet. Blood. 2010;115:453–74. Med. 2010;207:677–80. 3. Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, et al. Hematopoi- 21. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 etic stem-cell transplantation for acute leukemia in relapse or primary is upregulated on circulating hematopoietic stem cells and leukemia cells induction failure. J Clin Oncol. 2010;28:3730–8. to avoid phagocytosis. Cell. 2009;138:271–85. 4. Gregory TK, Wald D, Chen Y, Vermaat JM, Xiong Y, Tse W. Molecular prog- 22. Fu W, Li J, Zhang W, Li P. High expression of CD47 predicts adverse nostic markers for adult acute myeloid leukemia with normal cytogenet- prognosis in Chinese patients and suppresses immune response in ics. J Hematol Oncol. 2009;2:23. melanoma. Biomed Pharmacother. 2017;93:1190–6. 5. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, 23. Kong F, Gao F, Li H, Liu H, Zhang Y, Zheng R, et al. CD47: a potential et al. Diagnosis and management of AML in adults: 2017 ELN recommen- immunotherapy target for eliminating cancer cells. Clin Transl Oncol. dations from an international expert panel. Blood. 2017;129:424–47. 2016;18:1051–5. 6. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute 24. Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG, Hong AW, myeloid leukemia. J Clin Oncol. 2011;29:487–94. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 7. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid in the Hippo pathway. Nat Commun. 2015;6:8357. leukemia. Blood. 2005;106:1154–63. 25. Kim J, Guan KL. Amino acid signaling in TOR activation. Annu Rev Bio- 8. Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol chem. 2011;80:1001–32. Cell Biol. 2009;10:116–25. 26. Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecu- 9. Schwind S, Maharry K, Radmacher MD, Mrozek K, Holland KB, Margeson lar insights and advances in drug development. Br J Clin Pharmacol. D, et al. Prognostic significance of expression of a single microRNA, miR- 2016;82:943–56. 181a, in cytogenetically normal acute myeloid leukemia: a Cancer and 27. Hsu CL, Lee EX, Gordon KL, Paz EA, Shen WC, Ohnishi K, et al. MAP4K3 Leukemia Group B study. J Clin Oncol. 2010;28:5257–64. mediates amino acid-dependent regulation of autophagy via phospho- 10. Sun SM, Rockova V, Bullinger L, Dijkstra MK, Dohner H, Lowenberg B, et al. rylation of TFEB. Nat Commun. 2018;9:942. The prognostic relevance of miR-212 expression with survival in cytoge- 28. Xiong Y, Li Z, Ji M, Tan AC, Bemis J, Tse JV, et al. MIR29B regulates expres- netically and molecularly heterogeneous AML. Leukemia. 2013;27:100–6. sion of MLLT11 (AF1Q), an MLL fusion partner, and low MIR29B expression 11. Eisfeld AK, Marcucci G, Maharry K, Schwind S, Radmacher MD, Nicolet D, associates with adverse cytogenetics and poor overall survival in AML. Br et al. miR-3151 interplays with its host gene BAALC and independently J Haematol. 2011;153:753–7. affects outcome of patients with cytogenetically normal acute myeloid 29. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell mem- leukemia. Blood. 2012;120:249–58. brane to nucleus through SMAD proteins. Nature. 1997;390:465–71. 12. Middeke JM, Herold S, Rucker-Braun E, Berdel WE, Stelljes M, Kaufmann M, 30. Benito J, Shi Y, Szymanska B, Carol H, Boehm I, Lu H, et al. Pronounced et al. TP53 mutation in patients with high-risk acute myeloid leukaemia hypoxia in models of murine and human leukemia: high efficacy of treated with allogeneic haematopoietic stem cell transplantation. Br J hypoxia-activated prodrug PR-104. PLoS ONE. 2011;6:e23108. Haematol. 2016;172:914–22. 31. Zhang H, Akman HO, Smith EL, Zhao J, Murphy-Ullrich JE, Batuman OA. 13. Lai D, Visser-Grieve S, Yang X. Tumour suppressor genes in chemothera- Cellular response to hypoxia involves signaling via Smad proteins. Blood. peutic drug response. Biosci Rep. 2012;32:361–74. 2003;101:2253–60. 14. El-Deiry WS. The role of p53 in chemosensitivity and radiosensitivity. 32. Azizidoost S, Vijay V, Cogle CR, Khodadi E, Saki N. The role and clinical Oncogene. 2003;22:7486–95. implications of the endosteal niche and osteoblasts in regulating leuke- 15. Liu P, Hu Y, Ma L, Du M, Xia L, Hu Z. miR-425 inhibits melanoma metastasis mia. Clin Transl Oncol. 2017;19:1059–66. through repression of PI3 K-Akt pathway by targeting IGF-1. Biomed 33. Zhang Q, Zhang Q, Li Q, Liu B, Wang Y, Lin D, et al. Monitoring of WT1 Pharmacother. 2015;75:51–7. and its target gene IRF8 expression in acute myeloid leukemia and their 16. Ma J, Liu J, Wang Z, Gu X, Fan Y, Zhang W, et al. NF-kappaB-dependent significance. Int J Lab Hematol. 2015;37:e67–71. microRNA-425 upregulation promotes gastric cancer cell growth by 34. Kharas MG, Yusuf I, Scarfone VM, Yang VW, Segre JA, Huettner CS, et al. targeting PTEN upon IL-1beta induction. Mol Cancer. 2014;13:40. KLF4 suppresses transformation of pre-B cells by ABL oncogenes. Blood. 17. Yan YF, Gong FM, Wang BS, Zheng W. MiR-425-5p promotes tumor 2007;109:747–55. progression via modulation of CYLD in gastric cancer. Eur Rev Med Phar- 35. Morris VA, Cummings CL, Korb B, Boaglio S, Oehler VG. Deregulated KLF4 macol Sci. 2017;21:2130–6. expression in myeloid leukemias alters cell proliferation and differentia- 18. Di Leva G, Piovan C, Gasparini P, Ngankeu A, Taccioli C, Briskin D, et al. tion through MicroRNA and gene targets. Mol Cell Biol. 2016;36:559–73. Estrogen mediated-activation of miR-191/425 cluster modulates Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

Journal of Translational MedicineSpringer Journals

Published: Oct 1, 2018

There are no references for this article.