In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling
We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/96466 https://orcid.org/0000-0001-7603-8396 |
| _version_ | 1826217419056611328 |
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| author | Miller, Peter G. Al-Shahrour, Fatima Hartwell, Kimberly A. Chu, Lisa P. Jaras, Marcus Puram, Rishi V. Puissant, Alexandre Callahan, Kevin P. Ashton, John McConkey, Marie Poveromo, Luke P. Cowley, Glenn S. Kharas, Michael G. Labelle, Myriam Shterental, Sebastian Fujisaki, Joji Silberstein, Lev Alexe, Gabriela Al-Hajj, Muhammad A. Shelton, Christopher A. Armstrong, Scott A. Root, David E. Scadden, David T. Mukherjee, Siddhartha Stegmaier, Kimberly Jordan, Craig T. Ebert, Benjamin L. Hynes, Richard O |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Miller, Peter G. Al-Shahrour, Fatima Hartwell, Kimberly A. Chu, Lisa P. Jaras, Marcus Puram, Rishi V. Puissant, Alexandre Callahan, Kevin P. Ashton, John McConkey, Marie Poveromo, Luke P. Cowley, Glenn S. Kharas, Michael G. Labelle, Myriam Shterental, Sebastian Fujisaki, Joji Silberstein, Lev Alexe, Gabriela Al-Hajj, Muhammad A. Shelton, Christopher A. Armstrong, Scott A. Root, David E. Scadden, David T. Mukherjee, Siddhartha Stegmaier, Kimberly Jordan, Craig T. Ebert, Benjamin L. Hynes, Richard O |
| author_sort | Miller, Peter G. |
| collection | MIT |
| description | We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. |
| first_indexed | 2024-09-23T17:03:21Z |
| format | Article |
| id | mit-1721.1/96466 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:03:21Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/964662022-10-03T10:04:54Z In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling Miller, Peter G. Al-Shahrour, Fatima Hartwell, Kimberly A. Chu, Lisa P. Jaras, Marcus Puram, Rishi V. Puissant, Alexandre Callahan, Kevin P. Ashton, John McConkey, Marie Poveromo, Luke P. Cowley, Glenn S. Kharas, Michael G. Labelle, Myriam Shterental, Sebastian Fujisaki, Joji Silberstein, Lev Alexe, Gabriela Al-Hajj, Muhammad A. Shelton, Christopher A. Armstrong, Scott A. Root, David E. Scadden, David T. Mukherjee, Siddhartha Stegmaier, Kimberly Jordan, Craig T. Ebert, Benjamin L. Hynes, Richard O Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Hynes, Richard O. Labelle, Myriam We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant P01 CA108631) National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant RC1 CA145229) National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant R01 CA140292) National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant CA148180) 2015-04-08T18:29:38Z 2015-04-08T18:29:38Z 2013-06 2013-02 Article http://purl.org/eprint/type/JournalArticle 15356108 http://hdl.handle.net/1721.1/96466 Miller, Peter G., Fatima Al-Shahrour, Kimberly A. Hartwell, Lisa P. Chu, Marcus Jaras, Rishi V. Puram, Alexandre Puissant, et al. “In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling.” Cancer Cell 24, no. 1 (July 2013): 45–58. © 2013 Elsevier Inc. https://orcid.org/0000-0001-7603-8396 en_US http://dx.doi.org/10.1016/j.ccr.2013.05.004 Cancer Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier Open Archive |
| spellingShingle | Miller, Peter G. Al-Shahrour, Fatima Hartwell, Kimberly A. Chu, Lisa P. Jaras, Marcus Puram, Rishi V. Puissant, Alexandre Callahan, Kevin P. Ashton, John McConkey, Marie Poveromo, Luke P. Cowley, Glenn S. Kharas, Michael G. Labelle, Myriam Shterental, Sebastian Fujisaki, Joji Silberstein, Lev Alexe, Gabriela Al-Hajj, Muhammad A. Shelton, Christopher A. Armstrong, Scott A. Root, David E. Scadden, David T. Mukherjee, Siddhartha Stegmaier, Kimberly Jordan, Craig T. Ebert, Benjamin L. Hynes, Richard O In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| title | In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| title_full | In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| title_fullStr | In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| title_full_unstemmed | In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| title_short | In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| title_sort | in vivo rnai screening identifies a leukemia specific dependence on integrin beta 3 signaling |
| url | http://hdl.handle.net/1721.1/96466 https://orcid.org/0000-0001-7603-8396 |
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