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

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          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 better 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 optimal therapy between chemotherapy and allo-HSCT treatment regimens. Patients with low miR-425 expression may consider early allo-HSCT.

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          Most cited references24

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          Therapeutic advances in acute myeloid leukemia.

          The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.
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            Drug therapy for acute myeloid leukemia.

            Although improvement in outcomes has occurred in younger adults with acute myeloid leukemia (AML) during the past 4 decades, progress in older adults has been much less conspicuous, if at all. Approximately 50% to 75% of adults with AML achieve complete remission (CR) with cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only approximately 20% to 30% of the patients enjoy long-term disease survival. Various postremission strategies have been explored to eliminate minimal residual disease. The optimal dose, schedule, and number of cycles of postremission chemotherapy for most patients are not known. A variety of prognostic factors can predict outcome and include the karyotype of the leukemic cells and the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance and mutations in or over expressions of specific genes such as WT1, CEBPA, BAX and the ratio of BCL2 to BAX, BAALC, EVI1, KIT, and FLT3. Most recently, insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents and have ushered in an exciting new era of antileukemia therapy. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyl transferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, and apoptosis inhibitors.
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              Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure.

              Patients with acute leukemia refractory to induction or reinduction chemotherapy have poor prognoses if they do not undergo hematopoietic stem-cell transplantation (HSCT). However, HSCT when a patient is not in complete remission (CR) is of uncertain benefit. We hypothesized that pretransplantation variables may define subgroups that have a better prognosis. Overall, 2,255 patients who underwent transplantation for acute leukemia in relapse or with primary induction failure after myeloablative conditioning regimen between 1995 and 2004 were reported to the Center for International Blood and Marrow Transplant Research. The median follow-up of survivors was 61 months. We performed multivariate analysis of pretransplantation variables and developed a predictive scoring system for survival. The 3-year overall survival (OS) rates were 19% for acute myeloid leukemia (AML) and 16% for acute lymphoblastic leukemia (ALL). For AML, five adverse pretransplantation variables significantly influenced survival: first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics. For ALL, survival was worse with the following: first refractory or second or greater relapse, > or = 25% marrow blasts, cytomegalovirus-seropositive donor, and age of 10 years or older. Patients with AML who had a predictive score of 0 had 42% OS at 3 years, whereas OS was 6% for a score > or = 3. Patients with ALL who had a score of 0 or 1 had 46% 3-year OS but only 10% OS rate for a score > or = 3. Pretransplantation variables delineate subgroups with different outcomes. HSCT during relapse can achieve long-term survival in selected patients with acute leukemia.
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                Author and article information

                Contributors
                569081538@qq.com
                104712381@qq.com
                1356582671@qq.com
                1807737584@qq.com
                113639827@qq.com
                yaoy412@163.com
                307494877@qq.com
                745850431@qq.com
                173174828@qq.com
                1966859091@qq.com
                1263814061@qq.com
                107039582@qq.com
                msniu24@126.com
                lihmd@163.com
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                1 October 2018
                1 October 2018
                2018
                : 16
                : 267
                Affiliations
                [1 ]ISNI 0000 0000 9927 0537, GRID grid.417303.2, Blood Diseases Institute, Xuzhou Medical University, ; Xuzhou, Jiangsu China
                [2 ]GRID grid.413389.4, Department of Hematology, , Affiliated Hospital of Xuzhou Medical University, ; Xuzhou, Jiangsu China
                [3 ]ISNI 0000 0000 9927 0537, GRID grid.417303.2, Insititute of Nervous System Diseases, , Xuzhou Medical University, ; Xuzhou, Jiangsu China
                [4 ]GRID grid.440637.2, School of Physical Science and Technology, , ShanghaiTech University, ; Shanghai, China
                [5 ]ISNI 0000 0000 9247 7930, GRID grid.30055.33, School of Life Science & Medicine, , Dalian University of Technology, ; Panjin, China
                Author information
                http://orcid.org/0000-0002-7077-6467
                Article
                1647
                10.1186/s12967-018-1647-8
                6167790
                30285885
                d3a327df-f1e6-4ed5-8a68-40aa723c6702
                © The Author(s) 2018

                Open AccessThis 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.

                History
                : 21 August 2018
                : 26 September 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81670142
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Medicine
                mir-425,acute myeloid leukemia,prognosis,chemotherapy,allo-hsct
                Medicine
                mir-425, acute myeloid leukemia, prognosis, chemotherapy, allo-hsct

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