Post-transcriptional regulation of BCL2 mRNA by the RNA-binding protein ZFP36L1 in malignant B cells
The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The...
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| description | The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the 'maximum information coefficient' (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3' untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3' untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells. |
| doi_str_mv | 10.1371/journal.pone.0102625 |
| format | Article |
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These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the 'maximum information coefficient' (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3' untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3' untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0102625</identifier><identifier>PMID: 25014217</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3' Untranslated Regions ; Adenine ; Animals ; Apoptosis ; B cells ; B-Lymphocytes ; Biology and life sciences ; Butyrate Response Factor 1 - antagonists & inhibitors ; Butyrate Response Factor 1 - genetics ; Butyrate Response Factor 1 - metabolism ; Cell Line, Tumor ; Chemical properties ; Datasets ; Degradation ; DNA microarrays ; Electrophoretic mobility ; Fibroblasts ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene regulation ; Genes, Reporter ; Genetic aspects ; Genetic Vectors ; HEK293 Cells ; Humans ; Immunology ; Infections ; Inflammatory diseases ; Lentivirus - genetics ; Lentivirus - metabolism ; Leukemia ; Luciferase ; Luciferases - genetics ; Luciferases - metabolism ; Lymphocytes B ; Lymphoma ; Mammals ; Medicine and Health Sciences ; Messenger RNA ; Mice ; Nuclear Proteins - antagonists & inhibitors ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Pathogenesis ; Post-transcription ; Protein Binding ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Response Elements ; Ribonucleic acid ; RNA ; RNA Stability ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; RNA-binding protein ; RNA-Binding Proteins - antagonists & inhibitors ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Signal Transduction ; Target recognition ; Transcription (Genetics) ; Uridine ; Zinc ; Zinc finger proteins</subject><ispartof>PloS one, 2014-07, Vol.9 (7), p.e102625-e102625</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Zekavati et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Zekavati et al 2014 Zekavati et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-60ab48b18ac3d7b0b2ddcceb5f0da3008175a84ad28dd7ecc5730cd78a2733ff3</citedby><cites>FETCH-LOGICAL-c758t-60ab48b18ac3d7b0b2ddcceb5f0da3008175a84ad28dd7ecc5730cd78a2733ff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094554/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094554/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25014217$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zekavati, Anna</creatorcontrib><creatorcontrib>Nasir, Asghar</creatorcontrib><creatorcontrib>Alcaraz, Amor</creatorcontrib><creatorcontrib>Aldrovandi, Maceler</creatorcontrib><creatorcontrib>Marsh, Phil</creatorcontrib><creatorcontrib>Norton, John D</creatorcontrib><creatorcontrib>Murphy, John J</creatorcontrib><title>Post-transcriptional regulation of BCL2 mRNA by the RNA-binding protein ZFP36L1 in malignant B cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the 'maximum information coefficient' (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3' untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3' untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells.</description><subject>3' Untranslated Regions</subject><subject>Adenine</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>B cells</subject><subject>B-Lymphocytes</subject><subject>Biology and life sciences</subject><subject>Butyrate Response Factor 1 - antagonists & inhibitors</subject><subject>Butyrate Response Factor 1 - genetics</subject><subject>Butyrate Response Factor 1 - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Chemical properties</subject><subject>Datasets</subject><subject>Degradation</subject><subject>DNA microarrays</subject><subject>Electrophoretic mobility</subject><subject>Fibroblasts</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation</subject><subject>Genes, Reporter</subject><subject>Genetic aspects</subject><subject>Genetic Vectors</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immunology</subject><subject>Infections</subject><subject>Inflammatory diseases</subject><subject>Lentivirus - genetics</subject><subject>Lentivirus - metabolism</subject><subject>Leukemia</subject><subject>Luciferase</subject><subject>Luciferases - genetics</subject><subject>Luciferases - metabolism</subject><subject>Lymphocytes B</subject><subject>Lymphoma</subject><subject>Mammals</subject><subject>Medicine and Health Sciences</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Nuclear Proteins - antagonists & inhibitors</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Pathogenesis</subject><subject>Post-transcription</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Response Elements</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA Stability</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>RNA-binding protein</subject><subject>RNA-Binding Proteins - antagonists & inhibitors</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Target recognition</subject><subject>Transcription (Genetics)</subject><subject>Uridine</subject><subject>Zinc</subject><subject>Zinc finger proteins</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01v1DAQhiMEoqXwDxBYQkJwyOKPOM5eKm1XFFZa0ap8HLhYju1kXSX2YjuI_nucblrtoh5QDp7Yz7zOvJnJspcIzhBh6MO1G7wV3WzrrJ5BBHGJ6aPsGM0JzksMyeO9-Ch7FsI1hJRUZfk0O8IUogIjdpypSxdiHr2wQXqzjcYlTeB1O3RifAGuAWfLNQb91ZcFqG9A3GiQwrw2Vhnbgq13URsLfp5fknKNQAp70ZnWChvBGZC668Lz7EkjuqBfTOtJ9v3847fl53x98Wm1XKxzyWgV8xKKuqhqVAlJFKthjZWSUte0gUoQCCvEqKgKoXClFNNSUkagVKwSmBHSNOQke73T3XYu8MmgwBEtCooILEkiVjtCOXHNt970wt9wJwy_3XC-5cJHIzvNZT1HVcl0rTAqSsmqBjW4VpQ1iM210EnrdLptqHutpLbJxu5A9PDEmg1v3W9ewHlBaZEE3k0C3v0adIi8N2E0TFjthtvvpqiCjJYJffMP-nB1E9WKVICxjUv3ylGUL4pUDKGEoETNHqDSo3RvZOqmxqT9g4T3BwmJifpPbMUQAl99vfp_9uLHIft2j91o0cVNcN0w9l04BIsdKL0Lwevm3mQE-TgMd27wcRj4NAwp7dX-D7pPuut-8hfmfQMp</recordid><startdate>20140711</startdate><enddate>20140711</enddate><creator>Zekavati, Anna</creator><creator>Nasir, Asghar</creator><creator>Alcaraz, Amor</creator><creator>Aldrovandi, Maceler</creator><creator>Marsh, Phil</creator><creator>Norton, John D</creator><creator>Murphy, John J</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>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140711</creationdate><title>Post-transcriptional regulation of BCL2 mRNA by the RNA-binding protein ZFP36L1 in malignant B cells</title><author>Zekavati, Anna ; Nasir, Asghar ; Alcaraz, Amor ; Aldrovandi, Maceler ; Marsh, Phil ; Norton, John D ; Murphy, John J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-60ab48b18ac3d7b0b2ddcceb5f0da3008175a84ad28dd7ecc5730cd78a2733ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>3' Untranslated Regions</topic><topic>Adenine</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>B cells</topic><topic>B-Lymphocytes</topic><topic>Biology and life sciences</topic><topic>Butyrate Response Factor 1 - antagonists & inhibitors</topic><topic>Butyrate Response Factor 1 - genetics</topic><topic>Butyrate Response Factor 1 - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Chemical properties</topic><topic>Datasets</topic><topic>Degradation</topic><topic>DNA microarrays</topic><topic>Electrophoretic mobility</topic><topic>Fibroblasts</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene regulation</topic><topic>Genes, Reporter</topic><topic>Genetic aspects</topic><topic>Genetic Vectors</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Immunology</topic><topic>Infections</topic><topic>Inflammatory diseases</topic><topic>Lentivirus - genetics</topic><topic>Lentivirus - metabolism</topic><topic>Leukemia</topic><topic>Luciferase</topic><topic>Luciferases - genetics</topic><topic>Luciferases - metabolism</topic><topic>Lymphocytes B</topic><topic>Lymphoma</topic><topic>Mammals</topic><topic>Medicine and Health Sciences</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Nuclear Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zekavati, Anna</au><au>Nasir, Asghar</au><au>Alcaraz, Amor</au><au>Aldrovandi, Maceler</au><au>Marsh, Phil</au><au>Norton, John D</au><au>Murphy, John J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Post-transcriptional regulation of BCL2 mRNA by the RNA-binding protein ZFP36L1 in malignant B cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-07-11</date><risdate>2014</risdate><volume>9</volume><issue>7</issue><spage>e102625</spage><epage>e102625</epage><pages>e102625-e102625</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the 'maximum information coefficient' (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3' untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3' untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25014217</pmid><doi>10.1371/journal.pone.0102625</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-07, Vol.9 (7), p.e102625-e102625 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1544513063 |
| source | MEDLINE; Public Library of Science; Full-Text Journals in Chemistry (Open access); PubMed Central; Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | 3' Untranslated Regions Adenine Animals Apoptosis B cells B-Lymphocytes Biology and life sciences Butyrate Response Factor 1 - antagonists & inhibitors Butyrate Response Factor 1 - genetics Butyrate Response Factor 1 - metabolism Cell Line, Tumor Chemical properties Datasets Degradation DNA microarrays Electrophoretic mobility Fibroblasts Gene expression Gene Expression Regulation, Neoplastic Gene regulation Genes, Reporter Genetic aspects Genetic Vectors HEK293 Cells Humans Immunology Infections Inflammatory diseases Lentivirus - genetics Lentivirus - metabolism Leukemia Luciferase Luciferases - genetics Luciferases - metabolism Lymphocytes B Lymphoma Mammals Medicine and Health Sciences Messenger RNA Mice Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - genetics Nuclear Proteins - metabolism Pathogenesis Post-transcription Protein Binding Proteins Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Response Elements Ribonucleic acid RNA RNA Stability RNA, Small Interfering - genetics RNA, Small Interfering - metabolism RNA-binding protein RNA-Binding Proteins - antagonists & inhibitors RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Signal Transduction Target recognition Transcription (Genetics) Uridine Zinc Zinc finger proteins |
| title | Post-transcriptional regulation of BCL2 mRNA by the RNA-binding protein ZFP36L1 in malignant B cells |
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