The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia
The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1...
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| Format: | Article |
| Language: | en_US |
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Rockefeller University Press
2014
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| Online Access: | http://hdl.handle.net/1721.1/89125 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826214220350357504 |
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| author | Mansour, Marc R. Sanda, Takaomi Lawton, Lee N. Li, Xiaoyu Kreslavsky, Taras Novina, Carl D. Brand, Marjorie Gutierrez, Alejandro Kelliher, Michelle A. Jamieson, Catriona H. M. von Boehmer, Harald Young, Richard A. Look, A. Thomas |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Mansour, Marc R. Sanda, Takaomi Lawton, Lee N. Li, Xiaoyu Kreslavsky, Taras Novina, Carl D. Brand, Marjorie Gutierrez, Alejandro Kelliher, Michelle A. Jamieson, Catriona H. M. von Boehmer, Harald Young, Richard A. Look, A. Thomas |
| author_sort | Mansour, Marc R. |
| collection | MIT |
| description | The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor. |
| first_indexed | 2024-09-23T16:02:00Z |
| format | Article |
| id | mit-1721.1/89125 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:02:00Z |
| publishDate | 2014 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | mit-1721.1/891252022-10-02T05:48:07Z The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia Mansour, Marc R. Sanda, Takaomi Lawton, Lee N. Li, Xiaoyu Kreslavsky, Taras Novina, Carl D. Brand, Marjorie Gutierrez, Alejandro Kelliher, Michelle A. Jamieson, Catriona H. M. von Boehmer, Harald Young, Richard A. Look, A. Thomas Massachusetts Institute of Technology. Department of Biology Young, Richard A. The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor. National Cancer Institute (U.S.) (5P01CA109901) National Cancer Institute (U.S.) (5P01CA68484) National Cancer Institute (U.S.) (1K99CA157951) National Institutes of Health (U.S.). Intramural Research Program Center for Cancer Research (National Cancer Institute (U.S.)) 2014-09-02T14:30:25Z 2014-09-02T14:30:25Z 2013-07 2012-11 Article http://purl.org/eprint/type/JournalArticle 0022-1007 1540-9538 http://hdl.handle.net/1721.1/89125 Mansour, M. R., T. Sanda, L. N. Lawton, X. Li, T. Kreslavsky, C. D. Novina, M. Brand, et al. “The TAL1 Complex Targets the FBXW7 Tumor Suppressor by Activating miR-223 in Human T Cell Acute Lymphoblastic Leukemia.” Journal of Experimental Medicine 210, no. 8 (July 29, 2013): 1545–1557. https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1084/jem.20122516 Journal of Experimental Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Rockefeller University Press Rockefeller University Press |
| spellingShingle | Mansour, Marc R. Sanda, Takaomi Lawton, Lee N. Li, Xiaoyu Kreslavsky, Taras Novina, Carl D. Brand, Marjorie Gutierrez, Alejandro Kelliher, Michelle A. Jamieson, Catriona H. M. von Boehmer, Harald Young, Richard A. Look, A. Thomas The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia |
| title | The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia |
| title_full | The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia |
| title_fullStr | The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia |
| title_full_unstemmed | The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia |
| title_short | The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia |
| title_sort | tal1 complex targets the fbxw7 tumor suppressor by activating mir 223 in human t cell acute lymphoblastic leukemia |
| url | http://hdl.handle.net/1721.1/89125 https://orcid.org/0000-0001-8855-8647 |
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