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      Recurrent SETD2 mutation in NPM1-mutated acute myeloid leukemia

      1 , , 2 , 3 , , 2 , 3

      Biomarker Research

      BioMed Central

      SETD2 mutation, NPM1 mutation, Acute myeloid leukemia

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          Abstract

          SETD2 is the only methyltransferase for H3K36me3, and our previous study has firstly demonstrated that it functioned as one tumor suppressor in hematopoiesis. Consistent with it, SETD2 mutation, which led to its loss of function, was identified in AML. However, the distribution and function of SETD2 mutation in AML remained largely unknown. Herein, we integrated SETD2-mutated AML cases from our center and literature reports, and found that NPM1 mutation was the most common concomitant genetic alteration with SETD2 mutation in AML, with its frequency even higher than MLL rearrangement and AML1-ETO. Though this result indicated the cooperation of SETD2 and NPM1 mutations in leukemogenesis, our functional study showed that SETD2 was required for the proliferation of NPM1-mutated AML cell line OCI-AML3, but not MLL-rearranged AML cell line THP-1, via maintaining its direct target NPM1 expression, which was just opposite to its role of tumor suppressor. Therefore, we speculated that SETD2 possibly had two different faces in distinct subtypes and stages of AML.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s40364-020-00243-y.

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          Most cited references 13

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

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          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

            The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications. © 2012 AACR.
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              Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

                (2013)
              Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).
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                Author and article information

                Contributors
                drwjyu1977@zju.edu.cn
                hillhardaway@zju.edu.cn
                Journal
                Biomark Res
                Biomark Res
                Biomarker Research
                BioMed Central (London )
                2050-7771
                11 November 2020
                11 November 2020
                2020
                : 8
                Affiliations
                [1 ]GRID grid.268505.c, ISNI 0000 0000 8744 8924, Center Laboratory, Affiliated Secondary Hospital, , Zhejiang Chinese Medical University, ; Zhejiang, Hangzhou China
                [2 ]GRID grid.452661.2, ISNI 0000 0004 1803 6319, Department of Hematology, , The First Affiliated Hospital, Zhejiang University School of Medicine, ; #79 Qingchun Rd, Zhejiang, 310003 Hangzhou China
                [3 ]Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Zhejiang, Hangzhou China
                Article
                243
                10.1186/s40364-020-00243-y
                7659109
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81800199
                Award ID: 81670124
                Award Recipient :
                Categories
                Letter to the Editor
                Custom metadata
                © The Author(s) 2020

                setd2 mutation, npm1 mutation, acute myeloid leukemia

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