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      Clinical implications of recurrent gene mutations in acute myeloid leukemia

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          Abstract

          Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy characterized by recurrent gene mutations. Genomic heterogeneity, patients’ individual variability, and recurrent gene mutations are the major obstacles among many factors that impact treatment efficacy of the AML patients. With the application of cost- and time-effective next-generation sequencing (NGS) technologies, an enormous diversity of genetic mutations has been identified. The recurrent gene mutations and their important roles in acute myeloid leukemia (AML) pathogenesis have been studied extensively. In this review, we summarize the recent development on the gene mutation in patients with AML.

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          Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

          Jay Patel, Mithat Gonen, María Figueroa … (2012)
          Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
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            Assessment of Minimal Residual Disease in Standard-Risk AML

            Adam Ivey, Robert K. Hills, Michael A. Simpson … (2016)
            Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission.
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              Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission.

              M Corces-Zimmerman, Wan-Jen Hong, Irving L Weissman … (2014)
              Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in "landscaping" genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in "proliferative" genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.
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                Author and article information

                Contributors
                Jifeng Yu:
                ORCID: http://orcid.org/0000-0003-1217-4385
                yujifengzzu@163.com
                Zhongxing Jiang: Jiangzx@zzu.edu.cn
                Journal
                Journal ID (nlm-ta): Exp Hematol Oncol
                Journal ID (iso-abbrev): Exp Hematol Oncol
                Title: Experimental Hematology & Oncology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2162-3619
                Publication date (Electronic): 27 March 2020
                Publication date PMC-release: 27 March 2020
                Publication date Collection: 2020
                Volume: 9
                Electronic Location Identifier: 4
                Affiliations
                [1 ]GRID grid.412633.1, Department of Hematology, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China
                [2 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, Academy of Medical and Pharmaceutical Sciences, , Zhengzhou University, ; Zhengzhou, 450052 Henan China
                Author information
                http://orcid.org/0000-0003-1217-4385
                Article
                Publisher ID: 161
                DOI: 10.1186/s40164-020-00161-7
                PMC ID: 7099827
                PubMed ID: 32231866
                SO-VID: 3d5f6288-0182-432e-a1b8-8a153ad7f983
                Copyright © © The Author(s) 2020
                License:

                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.

                History
                Date received : 9 February 2020
                Date accepted : 17 March 2020
                Funding
                Funded by: Education Department of Henan Province (CN)
                Award ID: 19A320046
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004609, Foundation of Henan Educational Committee;
                Award ID: 20A320062
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: U1804192
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: recurrent gene mutation,acute myeloid leukemia (aml),flt3,cebpa,npm1,runx1,asxl1,tp53,idh1/2
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: recurrent gene mutation, acute myeloid leukemia (aml), flt3, cebpa, npm1, runx1, asxl1, tp53, idh1/2

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