In Vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling.

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.

DOI: 10.1016/j.ccr.2013.05.004

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@article{Miller2013InVR, title={In Vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling.}, author={Peter G Miller and F{\'a}tima Al-Shahrour and Kimberly A. Hartwell and Lisa P. Chu and Marcus J{\"a}r{\aa}s and Rishi V. Puram and Alexandre Puissant and Kevin P. Callahan and John M Ashton and Marie E. McConkey and Luke P Poveromo and Glenn S Cowley and Michael G Kharas and Myriam Labelle and Sebastian Shterental and Joji Fujisaki and Lev Silberstein and Gabriela Alexe and Muhammad A Al-Hajj and Christopher A Shelton and Scott A. Armstrong and David E. Root and David T Scadden and Richard O Hynes and Siddhartha Mukherjee and Kimberly Stegmaier and Craig T. Jordan and Benjamin L. Ebert}, journal={Cancer cell}, year={2013}, volume={24 1}, pages={45-58} }