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      PML‐RARα interferes with erythropoiesis by repressing LMO2 in acute promyelocytic leukaemia

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          Abstract

          The PMLRAR α fusion gene, generated by the t(15;17) chromosome translocation, is regarded as the initiating factor of acute promyelocytic leukaemia ( APL). In addition to the well‐known effects on blocking myeloid differentiation at the promyelocytic stage, promyelocytic leukaemia‐retinoic acid receptor α ( PMLRARα) has also been reported to interfere with multiple differentiation processes, including erythroid differentiation. However, the detailed molecular mechanism by which PMLRARα impairs erythropoiesis has not yet been fully addressed. By chromatin immunoprecipitation‐ PCR assay, we found that PMLRARα bound to the distal promoter region of LMO2 ( LIM‐only protein 2), a critical erythroid‐specific transcription factor. Luciferase reporter assays and qRTPCR results demonstrated that PMLRARα down‐regulated the expression of the LMO2 distal transcript through transrepressing its promoter activity. Analysis of gene expression profiling data from large cohorts of acute myeloid leukaemia ( AML) patients confirmed that LMO2 expressed at a markedly lower level in APL patients in comparison to non‐ APL AML patients. Further flow cytometry analysis demonstrated that PMLRARα inhibited erythropoietin‐induced erythroid differentiation by down‐regulating LMO2 expression. Our findings reveal a previously unidentified mechanism, by which PMLRARα interferes with erythropoiesis through directly targeting and transrepressing LMO2 expression in the development of APL.

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          Prognostically useful gene-expression profiles in acute myeloid leukemia.

          In patients with acute myeloid leukemia (AML) a combination of methods must be used to classify the disease, make therapeutic decisions, and determine the prognosis. However, this combined approach provides correct therapeutic and prognostic information in only 50 percent of cases. We determined the gene-expression profiles in samples of peripheral blood or bone marrow from 285 patients with AML using Affymetrix U133A GeneChips containing approximately 13,000 unique genes or expression-signature tags. Data analyses were carried out with Omniviz, significance analysis of microarrays, and prediction analysis of microarrays software. Statistical analyses were performed to determine the prognostic significance of cases of AML with specific molecular signatures. Unsupervised cluster analyses identified 16 groups of patients with AML on the basis of molecular signatures. We identified the genes that defined these clusters and determined the minimal numbers of genes needed to identify prognostically important clusters with a high degree of accuracy. The clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We identified several novel clusters, some consisting of specimens with normal karyotypes. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome. Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis. Copyright 2004 Massachusetts Medical Society
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            The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins.

            The LIM-only protein Lmo2, activated by chromosomal translocations in T-cell leukaemias, is normally expressed in haematopoiesis. It interacts with TAL1 and GATA-1 proteins, but the function of the interaction is unexplained. We now show that in erythroid cells Lmo2 forms a novel DNA-binding complex, with GATA-1, TAL1 and E2A, and the recently identified LIM-binding protein Ldb1/NLI. This oligomeric complex binds to a unique, bipartite DNA motif comprising an E-box, CAGGTG, followed approximately 9 bp downstream by a GATA site. In vivo assembly of the DNA-binding complex requires interaction of all five proteins and establishes a transcriptional transactivating complex. These data demonstrate one function for the LIM-binding protein Ldb1 and establish a function for the LIM-only protein Lmo2 as an obligatory component of an oligomeric, DNA-binding complex which may play a role in haematopoiesis.
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              Hypoxic regulation of erythropoiesis and iron metabolism.

              The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.
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                Author and article information

                Contributors
                kankanwang@shsmu.edu.cn
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                15 October 2018
                December 2018
                : 22
                : 12 ( doiID: 10.1111/jcmm.2018.22.issue-12 )
                : 6275-6284
                Affiliations
                [ 1 ] State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
                [ 2 ] Sino‐French Research Center for Life Sciences and Genomics Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
                Author notes
                [*] [* ] Correspondence

                Kankan Wang, State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

                Email: kankanwang@ 123456shsmu.edu.cn

                Author information
                http://orcid.org/0000-0001-7198-2134
                Article
                JCMM13917
                10.1111/jcmm.13917
                6237603
                30320491
                b0948618-58a2-4097-867e-9447ce1045de
                © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 January 2018
                : 06 July 2018
                : 27 August 2018
                Page count
                Figures: 4, Tables: 0, Pages: 10, Words: 6001
                Funding
                Funded by: National Natural Science Foundation Grants of China
                Award ID: 81770153
                Award ID: 81530003
                Award ID: 81300403
                Funded by: The National Key Research and Development Program
                Award ID: 2016YFC0902800
                Funded by: Academic Leader Program of Shanghai Science and Technology Committee
                Award ID: 2015137
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm13917
                December 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.1 mode:remove_FC converted:15.11.2018

                Molecular medicine
                acute promyelocytic leukaemia,erythropoiesis,lmo2,pml‐rarα
                Molecular medicine
                acute promyelocytic leukaemia, erythropoiesis, lmo2, pml‐rarα

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