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Prognostic Value of Mrna Expression of MAP4K Family in Acute Myeloid

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Prognostic Value of Mrna Expression of MAP4K Family in Acute Myeloid Original Article Technology in Cancer Research & Treatment Volume 18: 1-14 Prognostic Value of mRNA Expression ª The Author(s) 2019 Article reuse guidelines: of MAP4K Family in Acute sagepub.com/journals-permissions DOI: 10.1177/1533033819873927 Myeloid Leukemia journals.sagepub.com/home/tct Zhenjie Bai1 , Qingmei Yao2, Zhongyi Sun3, Fang Xu4, and Jicheng Zhou1 Abstract Background: Despite diverse functions in diseases, the prognostic potential of the family of mitogen-activated protein kinase kinase kinase kinase genes in acute myeloid leukemia remains unknown. Methods: The messenger RNA expression of the MAP4K family members in 151 patients with acute myeloid leukemia was extracted from the OncoLnc database. Data for gender, age, cytogenetic, leukocyte count, CD34, FAB classification, RUNX1, and TP53 were provided by the University of California–Santa Cruz Xena platform. Kaplan-Meier analysis and Cox regression model provided an estimate of the hazard ratio with 95% confidence intervals for overall survival. Results: Analysis demonstrated favorable overall survival in patients with acute myeloid leukemia attributing to high expression of MAP4K3, MAP4K4, and MAP4K5 and low expression of MAP4K1 (adjusted P ¼ .005, P ¼ .022, P ¼ .002, and P ¼ .024; adjusted hazard ratio ¼ 0.490, 95% confidence interval ¼ 0.297-0.809, hazard ratio ¼ 0.598, 95% confidence interval ¼ 0.385-0.928, hazard ratio ¼ 0.490, 95% confidence interval ¼ 0.310-0.776, and hazard ratio ¼ 0.615, 95% confidence interval ¼ 0.403-0.938, respectively). Combining the high-expressing MAP4K3, MAP4K4, and MAP4K5 with the low-expressing MAP4K1 in a joint effect analysis predicted a favorable prognosis of overall survival in acute myeloid leukemia. Conclusion: High expression of MAP4K3, MAP4K4, and MAP4K5 combined with low expression of MAP4K1 can serve as a sensitive tool to predict favorable overall survival in patients with acute myeloid leukemia. Keywords MAP4K, acute myeloid leukemia, prognosis Abbreviations AML, acute myeloid leukemia; BP, biological process; CC, cellular component; CI, confidence interval; JNK, Janus kinase; KEGG, Kyoto Encyclopedia of Genes; HR, hazard ratio; MAP4K, mitogen-activated protein kinase kinase kinase kinase; MF, molecular function; mRNA, messenger RNA; GO, Gene Ontology; NF-kB, nuclear factor kB; HPK1, hematopoietic progenitor kinase 1; OS, overall survival; SLE, systemic lupus erythematosus Received: May 27, 2019; Revised: August 11, 2019; Accepted: August 13, 2019. Introduction 1 Department of Medical Hematopathy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China Acute myeloid leukemia (AML) is a malignant clonal disease 2 School of Preclinical Medicine Guangxi Medical University, Nanning, Guangxi, P.R. China of the hematopoietic stem cells. Among the malignant tumor 3 mortality rates in China, leukemia ranks sixth in men and Department of Medical Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China seventh in women. Acute myeloid leukemia is the most com- 4 The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, mon form of leukemia in adults accounting for 32.4% of new P.R. China cases with leukemia and 43.8% of leukemia-related deaths. The International Classification of Childhood Cancer reported that Corresponding Author: % Jicheng Zhou, Department of Medical Hematopathy, The First Affiliated leukemia accounts for 29 of all childhood cancers. The US Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning 2007 to 2013 report on the common childhood cancers predicts 530021, Guangxi, China. that the 5-year survival rate of patients with AML diagnosed Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Technology in Cancer Research & Treatment between 0 and 14 years is the lowest at 65.1%,posinga of MAP4K subunits in clinical patients was downloaded from serious threat to the health of children.1 The main treatments the Metabolic gEne RApid Visualizer (http://merav.wi.mit. for AML include chemotherapy, radiation therapy, molecular edu/SearchByGenes.html, accessed by January 30, 2019).25 therapy, and allogeneic hematopoietic stem cell transplanta- Boxplots were created on GraphPad Prism v.7.0 (La Jolla, tion.2,3 Prognosis and treatment options for AML are deter- California). mined by the effective detection of genetic markers. Studies have shown that genes, including NPM1, FLT3, C-KIT, 4 5 AML1-ETO, RUNX1, TP53, MLL-TD, CBFB/MYH11, Survival and Joint Effect Analyses TET2, DNMT3A, JAK-STAT,andCXCR4,6 are associated with prognosis of AML. However, there exists a gap in our For each MAP4K mRNA, patients were divided into high- and understanding of the prognostic value of family of MAP4K low-expression groups according to a 50th percentile cutoff. genes in AML. Correlation between the 6 MAP4K genes and survival of Mitogen-activated protein kinase kinase kinase kinase patients with AML was determined by Kaplan-Meier analysis (MAP4Ks) belong to the family of mammalian ste20-like and a log-rank test. Cox proportional hazard regression model serine/threonine kinases. MAP4Ks reported so far include was used to adjusting the P values, hazard ratios (HRs), and MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/ 95% confidence intervals (CIs) of the clinical information. HGK, MAP4K5/KHS,andMAP4K6/MINK1.7 Through the Significant genes from the joint effect analysis were grouped activation of the MAP3K–MAP2K cascade, MAP4Ks can into the better OS, the worse OS, and the other groups induce Janus kinase (JNK) activation, which is vital for (Tables 1-3). medullary differentiation of hematopoietic tissue.7-10 The MAP4K1 is reported to be involved with various adapter proteins, such as CARD11, HSI, HIP-55, GRB2, LAT, SLP- Statistical Analyses 76, CRK, and BAM32, and plays important roles in autoim- mune diseases, tumorigenesis, apoptosis, inhibition of TCR/ Kaplan-Meier survival analysis and the log-rank test were BCR signaling, and T/B/dendritic cell-mediated immune used to calculate OS and P values for all associations. A Cox responses. Both MAP4K1 and MAP4K3 are involved in the proportional hazards regression model was used for univari- progression of immune diseases. While MAP4K1 is down- ate and multivariate survival analyses. Hazard ratios and 95% regulated,8 MAP4K3 is upregulated in systemic lupus erythe- CIs were calculated with the Cox proportional hazards matosus (SLE).11 Upregulation of MAP4K3 and MAP4K4 regression model, which was used to adjust for age, cytoge- promotes metastasis of breast cancer cells12,13 and liver can- netic, FAB classification, RUNX1, and TP53. P values of OS cer cells.14,15 Elevated expression of MAP4K2 boosted tumor were calculated with the Cox proportional hazards regression proliferation in diffuse large B-cell lymphoma16 and UV model, which indicates whether there is a difference in OS resistance in melanoma cells.17,18 While downregulation of rate. The best prognostic group in each combination was used MAP4K5 promoted the progression of pancreatic cancer,19 it as a reference, comparing with the poor prognosis group and inhibited the activity of BCR-ABL in CML.20 MINK1 was the moderate prognosis group, respectively, and 2 P values reported to be involved in cell division and dendritic structure were obtained. Statistical analyses were performed on SPSS integrity and synaptic transmission.21,22 Nevertheless, the v.22.0 software (IBM, Chicago, Illinois). Vertical scatter plot relationship between MAP4K family and patients with AML of MAP4K mRNA expression and survival curves for remains understudied. In this study, the prognostic value of MAP4K family were generated in GraphPad Prism v.7.0 individual MAP4K messenger RNA (mRNA) expression was (La Jolla, California). evaluated by combined effect analysis using data from the OncoLnc database and the University of California, Santa Cruz Xena. Analysis of Functional Enrichment and Pearson Correlation Materials and Methods The Database for Annotation, Visualization, and Integrated Discovery V6.8 (https://david.ncifcrf.gov/tools.jsp, accessed Data February 10, 2019), Gene Ontology (GO) functional analysis Clinical information including events, survival time, death sta- and Kyoto Encyclopedia of Genes and Genomes (KEGG) path- tus, age, gender, cytogenetic, leukocyte count, CD34, FAB way analysis were used to reveal functional enrichment.26,27 classification, RUNX1, and TP53 from 151 patients with AML The GO annotations included molecular function (MF), cellu- was extracted from the University of California, Santa Cruz lar component (CC), and biological process (BP). GeneMA- Xena (https://xenabrowser.net/datapages/, accessed by January NIA (http://genemania.org/; accessed February 11, 2019)28 15, 2019).23 Transcript expression of the MAP4K family in was used to reveal interactions among MAP4K family mem- AML tissues was obtained from OncoLnc (http://www. bers, and correlations were identified by Pearson correlation oncolnc.org/, accessed by January 15, 2019).24 The expression coefficient analysis. Bai et al 3 Table 1. Group of 2 Selected
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