Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia
The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature...
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| Veröffentlicht in: | Leukemia 2017-08, Vol.31 (8), p.1798-1807 |
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| creator | Liau, W S Tan, S H Ngoc, P C T Wang, C Q Tergaonkar, V Feng, H Gong, Z Osato, M Look, A T Sanda, T |
| description | The transcription factor
TAL1/SCL
is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the
GIMAP
locus, which resides within an insulated chromosomal locus in T-ALL cells. The
GIMAP
genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The
GIMAP
enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human
GIMAP
genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the
GIMAP
enhancer contributes to T-cell leukemogenesis. |
| doi_str_mv | 10.1038/leu.2016.392 |
| format | Article |
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TAL1/SCL
is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the
GIMAP
locus, which resides within an insulated chromosomal locus in T-ALL cells. The
GIMAP
genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The
GIMAP
enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human
GIMAP
genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the
GIMAP
enhancer contributes to T-cell leukemogenesis.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2016.392</identifier><identifier>PMID: 28028313</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 14/63 ; 38 ; 631/136/232/2058 ; 631/67/1990/283/2125 ; 631/67/395 ; 631/67/68 ; 64/116 ; 692/420/755 ; Aberration ; Activation ; Acute lymphoblastic leukemia ; Acute lymphocytic leukemia ; Animals ; Basic Helix-Loop-Helix Transcription Factors - physiology ; Cancer Research ; Care and treatment ; Cell Line, Tumor ; Critical Care Medicine ; Differentiation ; Enhancer Elements, Genetic - physiology ; GATA-3 protein ; Genes ; Genetic transformation ; GTP-Binding Proteins - genetics ; Hematology ; Hematopoietic stem cells ; Humans ; Intensive ; Internal Medicine ; Leukemia ; Leukemogenesis ; Loci ; Lymphatic leukemia ; Lymphocytes ; Lymphocytes T ; Medicine ; Medicine & Public Health ; Membrane Proteins - genetics ; Mice ; Mice, Inbred C57BL ; Multigene Family ; Oncology ; original-article ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - etiology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Proteins ; Proto-Oncogene Proteins - physiology ; Runx1 protein ; Stem cells ; T cell receptors ; T cells ; T-Cell Acute Lymphocytic Leukemia Protein 1 ; Thymocytes ; Thymus ; Transcription factors ; Transcription Factors - physiology ; Tumorigenesis ; Zebrafish</subject><ispartof>Leukemia, 2017-08, Vol.31 (8), p.1798-1807</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2017</rights><rights>Macmillan Publishers Limited, part of Springer Nature. 2017.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c576t-6306abf9fe8c2c6ad9046573e987ca5254c855c5a679806e258388d814af64d93</citedby><cites>FETCH-LOGICAL-c576t-6306abf9fe8c2c6ad9046573e987ca5254c855c5a679806e258388d814af64d93</cites><orcidid>0000-0003-1621-4954 ; 0000-0003-1318-821X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2016.392$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2016.392$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28028313$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liau, W S</creatorcontrib><creatorcontrib>Tan, S H</creatorcontrib><creatorcontrib>Ngoc, P C T</creatorcontrib><creatorcontrib>Wang, C Q</creatorcontrib><creatorcontrib>Tergaonkar, V</creatorcontrib><creatorcontrib>Feng, H</creatorcontrib><creatorcontrib>Gong, Z</creatorcontrib><creatorcontrib>Osato, M</creatorcontrib><creatorcontrib>Look, A T</creatorcontrib><creatorcontrib>Sanda, T</creatorcontrib><title>Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The transcription factor
TAL1/SCL
is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the
GIMAP
locus, which resides within an insulated chromosomal locus in T-ALL cells. The
GIMAP
genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The
GIMAP
enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human
GIMAP
genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the
GIMAP
enhancer contributes to T-cell leukemogenesis.</description><subject>13/106</subject><subject>14/63</subject><subject>38</subject><subject>631/136/232/2058</subject><subject>631/67/1990/283/2125</subject><subject>631/67/395</subject><subject>631/67/68</subject><subject>64/116</subject><subject>692/420/755</subject><subject>Aberration</subject><subject>Activation</subject><subject>Acute lymphoblastic leukemia</subject><subject>Acute lymphocytic leukemia</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Transcription Factors - physiology</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Critical Care Medicine</subject><subject>Differentiation</subject><subject>Enhancer Elements, Genetic - physiology</subject><subject>GATA-3 protein</subject><subject>Genes</subject><subject>Genetic transformation</subject><subject>GTP-Binding Proteins - genetics</subject><subject>Hematology</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Leukemogenesis</subject><subject>Loci</subject><subject>Lymphatic leukemia</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Proteins - genetics</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Multigene Family</subject><subject>Oncology</subject><subject>original-article</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - etiology</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Runx1 protein</subject><subject>Stem cells</subject><subject>T cell receptors</subject><subject>T cells</subject><subject>T-Cell Acute Lymphocytic Leukemia Protein 1</subject><subject>Thymocytes</subject><subject>Thymus</subject><subject>Transcription factors</subject><subject>Transcription Factors - physiology</subject><subject>Tumorigenesis</subject><subject>Zebrafish</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9ks1rFDEYxgdR7LZ68ywBQXpw1nxMMslFWIrWQkUP9RwymXd2UmeTNZkp7H9vxq11V4rkEMj7e568X0XxiuAlwUy-H2BaUkzEkin6pFiQqhYl55w8LRZYyroUilYnxWlKtxjPQfG8OKESU8kIWxRp1UCMxo_I2NHdmdEFj0KHxh7Q5dWX1TcEvjfeQkTNDgVvwxq8s2jMmmSj2_4WdFkcYkLOo5vSwjBkt2kENOw22z40g0lj1uRMf8DGmRfFs84MCV7e32fF908fby4-l9dfL68uVtel5bUYS8GwME2nOpCWWmFahSvBawZK1tZwyisrObfciFpJLIByyaRsJalMJ6pWsbPiw953OzUbaC34nPWgt9FtTNzpYJw-jnjX63W405xTRRXLBuf3BjH8nCCNeuPSXJ7xEKakieSsrvK3IqNv_kFvwxR9Lk9TQThnlCvyP4ooyolURLK_1NoMoJ3vQs7Ozl_rVaVUnccoZaaWj1D5tLnHNnjoXH4_Erw9EPRghrFPYZjmCaZj8N0etDGkFKF7aBnBet45nSep553Teecy_vqwzQ_wnyXLQLkHUg75NcSDqh8z_AVBRt8q</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Liau, W S</creator><creator>Tan, S H</creator><creator>Ngoc, P C T</creator><creator>Wang, C Q</creator><creator>Tergaonkar, V</creator><creator>Feng, H</creator><creator>Gong, Z</creator><creator>Osato, M</creator><creator>Look, A T</creator><creator>Sanda, T</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</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>C1K</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>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1621-4954</orcidid><orcidid>https://orcid.org/0000-0003-1318-821X</orcidid></search><sort><creationdate>20170801</creationdate><title>Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia</title><author>Liau, W S ; Tan, S H ; Ngoc, P C T ; Wang, C Q ; Tergaonkar, V ; Feng, H ; Gong, Z ; Osato, M ; Look, A T ; Sanda, T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c576t-6306abf9fe8c2c6ad9046573e987ca5254c855c5a679806e258388d814af64d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/106</topic><topic>14/63</topic><topic>38</topic><topic>631/136/232/2058</topic><topic>631/67/1990/283/2125</topic><topic>631/67/395</topic><topic>631/67/68</topic><topic>64/116</topic><topic>692/420/755</topic><topic>Aberration</topic><topic>Activation</topic><topic>Acute lymphoblastic leukemia</topic><topic>Acute lymphocytic leukemia</topic><topic>Animals</topic><topic>Basic Helix-Loop-Helix Transcription Factors - physiology</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Cell Line, Tumor</topic><topic>Critical Care Medicine</topic><topic>Differentiation</topic><topic>Enhancer Elements, Genetic - physiology</topic><topic>GATA-3 protein</topic><topic>Genes</topic><topic>Genetic transformation</topic><topic>GTP-Binding Proteins - genetics</topic><topic>Hematology</topic><topic>Hematopoietic stem cells</topic><topic>Humans</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Leukemia</topic><topic>Leukemogenesis</topic><topic>Loci</topic><topic>Lymphatic leukemia</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane Proteins - genetics</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Multigene Family</topic><topic>Oncology</topic><topic>original-article</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - etiology</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - physiology</topic><topic>Runx1 protein</topic><topic>Stem cells</topic><topic>T cell receptors</topic><topic>T cells</topic><topic>T-Cell Acute Lymphocytic Leukemia Protein 1</topic><topic>Thymocytes</topic><topic>Thymus</topic><topic>Transcription factors</topic><topic>Transcription Factors - physiology</topic><topic>Tumorigenesis</topic><topic>Zebrafish</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liau, W S</creatorcontrib><creatorcontrib>Tan, S H</creatorcontrib><creatorcontrib>Ngoc, P C T</creatorcontrib><creatorcontrib>Wang, C Q</creatorcontrib><creatorcontrib>Tergaonkar, V</creatorcontrib><creatorcontrib>Feng, H</creatorcontrib><creatorcontrib>Gong, Z</creatorcontrib><creatorcontrib>Osato, M</creatorcontrib><creatorcontrib>Look, A T</creatorcontrib><creatorcontrib>Sanda, T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liau, W S</au><au>Tan, S H</au><au>Ngoc, P C T</au><au>Wang, C Q</au><au>Tergaonkar, V</au><au>Feng, H</au><au>Gong, Z</au><au>Osato, M</au><au>Look, A T</au><au>Sanda, T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>31</volume><issue>8</issue><spage>1798</spage><epage>1807</epage><pages>1798-1807</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>The transcription factor
TAL1/SCL
is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the
GIMAP
locus, which resides within an insulated chromosomal locus in T-ALL cells. The
GIMAP
genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The
GIMAP
enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human
GIMAP
genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the
GIMAP
enhancer contributes to T-cell leukemogenesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28028313</pmid><doi>10.1038/leu.2016.392</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-1621-4954</orcidid><orcidid>https://orcid.org/0000-0003-1318-821X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Leukemia, 2017-08, Vol.31 (8), p.1798-1807 |
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| language | eng |
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| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 13/106 14/63 38 631/136/232/2058 631/67/1990/283/2125 631/67/395 631/67/68 64/116 692/420/755 Aberration Activation Acute lymphoblastic leukemia Acute lymphocytic leukemia Animals Basic Helix-Loop-Helix Transcription Factors - physiology Cancer Research Care and treatment Cell Line, Tumor Critical Care Medicine Differentiation Enhancer Elements, Genetic - physiology GATA-3 protein Genes Genetic transformation GTP-Binding Proteins - genetics Hematology Hematopoietic stem cells Humans Intensive Internal Medicine Leukemia Leukemogenesis Loci Lymphatic leukemia Lymphocytes Lymphocytes T Medicine Medicine & Public Health Membrane Proteins - genetics Mice Mice, Inbred C57BL Multigene Family Oncology original-article Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - etiology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics Proteins Proto-Oncogene Proteins - physiology Runx1 protein Stem cells T cell receptors T cells T-Cell Acute Lymphocytic Leukemia Protein 1 Thymocytes Thymus Transcription factors Transcription Factors - physiology Tumorigenesis Zebrafish |
| title | Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia |
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