In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

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...

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Bibliographic Details
Main Authors: 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
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:en_US
Published: Elsevier 2015
Online Access:http://hdl.handle.net/1721.1/96466
https://orcid.org/0000-0001-7603-8396
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Summary: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.

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