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      The Differential Expression of CD47 may be Related to the Pathogenesis From Myelodysplastic Syndromes to Acute Myeloid Leukemia

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          Abstract

          Myelodysplastic syndrome (MDS) can lead to the development of peripheral blood cytopenia and abnormal cell morphology. MDS has the potential to evolve into AML and can lead to reduced survival. CD47, a member of the immunoglobulin family, is one molecule that is overexpressed in a variety of cancer cells and is associated with clinical features and poor prognosis in a variety of malignancies. In this study, we analyzed the expression and function of CD47 in MDS and AML, and further analyzed its role in other tumors. Our analysis revealed significantly low CD47 expression in MDS and significantly high expression in AML. Further analysis of the function or pathway of CD47 from different perspectives identified a relationship to the immune response, cell growth, and other related functions or pathways. The relationship between CD47 and other tumors was analyzed from four aspects: DNA methyltransferase, TMB, MSI, and tumor cell stemness. Changes in gene expression levels have a known association with aberrant DNA methylation, and this methylation is the main mechanism of tumor suppressor gene silencing and clonal variation during the evolution of MDS to AML. Taken together, our findings support the hypothesis that the differential expression of CD47 might be related to the transformation of MDS to AML.

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          Most cited references35

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          The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

          The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.
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            CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells.

            Acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells (LSC). We hypothesized that increased CD47 expression on human AML LSC contributes to pathogenesis by inhibiting their phagocytosis through the interaction of CD47 with an inhibitory receptor on phagocytes. We found that CD47 was more highly expressed on AML LSC than their normal counterparts, and that increased CD47 expression predicted worse overall survival in three independent cohorts of adult AML patients. Furthermore, blocking monoclonal antibodies directed against CD47 preferentially enabled phagocytosis of AML LSC and inhibited their engraftment in vivo. Finally, treatment of human AML LSC-engrafted mice with anti-CD47 antibody depleted AML and targeted AML LSC. In summary, increased CD47 expression is an independent, poor prognostic factor that can be targeted on human AML stem cells with blocking monoclonal antibodies capable of enabling phagocytosis of LSC.
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              DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

              Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                31 March 2022
                2022
                : 12
                : 872999
                Affiliations
                [1] 1 Haematology Department of Ningbo First Hospital, Ningbo Clinical Research Center for Hematologic Malignancies , Ningbo, China
                [2] 2 Haematology Department, The Affiliated Hospital of Medical School of Ningbo University , Ningbo, China
                [3] 3 Medical Research Center of Ningbo First Hospital , Ningbo, China
                [4] 4 Stem Cell Transplantation Laboratory of Ningbo First Hospital, Institute of Hematology of Ningbo First Hospital , Ningbo, China
                Author notes

                Edited by: Ye Wang, The Second Affiliated Hospital of Medical College of Qingdao University, China

                Reviewed by: Zhijian Xiao, Chinese Academy of Medical Sciences and Peking Union Medical College, China; Na Li, Peter MacCallum Cancer Centre, Australia; Di Yang, Huazhong University of Science and Technology, China

                *Correspondence: Guifang Ouyang, oygf@ 123456nbdyyy.com

                This article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.872999
                9008711
                35433462
                0990d44b-6b5b-4479-b48a-d70603088adf
                Copyright © 2022 Yan, Lai, Zhou, Yang, Ge, Zhou, Shi, Xu and Ouyang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 February 2022
                : 07 March 2022
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 35, Pages: 8, Words: 2853
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                mds,aml,cd47,dna methylation,expression
                Oncology & Radiotherapy
                mds, aml, cd47, dna methylation, expression

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