MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO
A network of lineage-specific transcription factors and microRNAs tightly regulates differentiation of hematopoietic stem cells along the distinct lineages. Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master reg...
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| creator | Kohrs, Nicole Kolodziej, Stephan Kuvardina, Olga N Herglotz, Julia Yillah, Jasmin Herkt, Stefanie Piechatzek, Alexander Salinas Riester, Gabriela Lingner, Thomas Wichmann, Christian Bonig, Halvard Seifried, Erhard Platzbecker, Uwe Medyouf, Hind Grez, Manuel Lausen, Jörn |
| description | A network of lineage-specific transcription factors and microRNAs tightly regulates differentiation of hematopoietic stem cells along the distinct lineages. Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product. |
| doi_str_mv | 10.1371/journal.pgen.1005946 |
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Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1005946</identifier><identifier>PMID: 26990877</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acute myelocytic leukemia ; Biology and life sciences ; Cell Differentiation - genetics ; Cell Lineage ; Cloning ; Core Binding Factor Alpha 2 Subunit - biosynthesis ; Core Binding Factor Alpha 2 Subunit - genetics ; Epigenetics ; Experiments ; Gene expression ; Gene Expression Regulation, Leukemic ; Gene Regulatory Networks - genetics ; Genetic aspects ; Health aspects ; Hematopoietic stem cells ; Humans ; Leukemia ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - pathology ; Medicine and Health Sciences ; Megakaryocytes - cytology ; MicroRNA ; MicroRNAs ; MicroRNAs - biosynthesis ; MicroRNAs - genetics ; Mutation ; Oncogene Proteins, Fusion - biosynthesis ; Oncogene Proteins, Fusion - genetics ; Proteins ; Research and analysis methods ; Transcription factors</subject><ispartof>PLoS genetics, 2016-03, Vol.12 (3), p.e1005946-e1005946</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Kohrs N, Kolodziej S, Kuvardina ON, Herglotz J, Yillah J, Herkt S, et al. (2016) MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO. PLoS Genet 12(3): e1005946. doi:10.1371/journal.pgen.1005946</rights><rights>2016 Kohrs et al 2016 Kohrs et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Kohrs N, Kolodziej S, Kuvardina ON, Herglotz J, Yillah J, Herkt S, et al. (2016) MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO. 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Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product.</description><subject>Acute myelocytic leukemia</subject><subject>Biology and life sciences</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Lineage</subject><subject>Cloning</subject><subject>Core Binding Factor Alpha 2 Subunit - biosynthesis</subject><subject>Core Binding Factor Alpha 2 Subunit - genetics</subject><subject>Epigenetics</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Gene Regulatory Networks - genetics</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Medicine and Health Sciences</subject><subject>Megakaryocytes - cytology</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - biosynthesis</subject><subject>MicroRNAs - genetics</subject><subject>Mutation</subject><subject>Oncogene Proteins, Fusion - biosynthesis</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Proteins</subject><subject>Research and analysis methods</subject><subject>Transcription factors</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk99v0zAQxyMEYmPwHyCIhITGQ1u7tuP4BWnaClTaVqlsiCcsx7mkLmlc7GTa_nvcNpsatIchy_Kvz319d_ZF0VuMhphwPFra1tWqGq5LqIcYISZo8iw6xIyRAaeIPt-bH0SvvF8iRFgq-MvoYJwIgVLOD6NfF2aOKR1RhuPJ7dqB98bW8dTHc9iuII-zu3h-ffkTx2etM3UZX0Cpfit3Z9fWgDc-VnUenxnftC7bw0eTq9nr6EWhKg9vuvEouv4yuTr9NjiffZ2enpwPNGeiGTCVAwahC6WIAoFIxjKhWVakGLSmZIyREEQTQtMsQaFjwZI8BD1GCaYJIkfR-53uurJedqnxEvMUE4GFSAIx3RG5VUu5dmYVIpBWGbndsK6UyjVGVyBzNIaMgSpoTikvlCgozhMFLM9UMgYctD53t7XZCnINdeNU1RPtn9RmIUt7IykXKaUkCBx3As7-acE3cmW8hqpSNdh26zcXCePJU1DOCBd8G-KHf9DHE9FRpQqxmrqwwUW9EZUnwb8gxmgaqOEjVGg5rIy2NRQm7PcMPvUMAtPAbVOq1ns5_T7_D_by6ezsR5_9uMcuQFXNwtuqbcKX9n2Q7kDtrPcOioe3w0huqus-c3JTXbKrrmD2bv_dH4zuy4n8BYk9G6U</recordid><startdate>20160318</startdate><enddate>20160318</enddate><creator>Kohrs, Nicole</creator><creator>Kolodziej, Stephan</creator><creator>Kuvardina, Olga N</creator><creator>Herglotz, Julia</creator><creator>Yillah, Jasmin</creator><creator>Herkt, Stefanie</creator><creator>Piechatzek, Alexander</creator><creator>Salinas Riester, Gabriela</creator><creator>Lingner, Thomas</creator><creator>Wichmann, Christian</creator><creator>Bonig, Halvard</creator><creator>Seifried, Erhard</creator><creator>Platzbecker, Uwe</creator><creator>Medyouf, Hind</creator><creator>Grez, Manuel</creator><creator>Lausen, Jörn</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160318</creationdate><title>MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO</title><author>Kohrs, Nicole ; Kolodziej, Stephan ; Kuvardina, Olga N ; Herglotz, Julia ; Yillah, Jasmin ; Herkt, Stefanie ; Piechatzek, Alexander ; Salinas Riester, Gabriela ; Lingner, Thomas ; Wichmann, Christian ; Bonig, Halvard ; Seifried, Erhard ; Platzbecker, Uwe ; Medyouf, Hind ; Grez, Manuel ; Lausen, Jörn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c759t-5ade1e9cfaa3ae903b5b9c5bf81ecc43210993c3348b608b61956d10020614603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acute myelocytic leukemia</topic><topic>Biology and life sciences</topic><topic>Cell Differentiation - 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Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26990877</pmid><doi>10.1371/journal.pgen.1005946</doi><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Acute myelocytic leukemia Biology and life sciences Cell Differentiation - genetics Cell Lineage Cloning Core Binding Factor Alpha 2 Subunit - biosynthesis Core Binding Factor Alpha 2 Subunit - genetics Epigenetics Experiments Gene expression Gene Expression Regulation, Leukemic Gene Regulatory Networks - genetics Genetic aspects Health aspects Hematopoietic stem cells Humans Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Medicine and Health Sciences Megakaryocytes - cytology MicroRNA MicroRNAs MicroRNAs - biosynthesis MicroRNAs - genetics Mutation Oncogene Proteins, Fusion - biosynthesis Oncogene Proteins, Fusion - genetics Proteins Research and analysis methods Transcription factors |
| title | MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO |
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