In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling
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Hynes_InVivo RNAi.pdf
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Author(s)
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
Date Issued
June 2013
Journal
Cancer Cell
Publisher
Elsevier
Citation
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.
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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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.
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DOI of Published Version
https://doi.org/10.1016/j.ccr.2013.05.004
