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

Miller, Peter G.; Al-Shahrour, Fatima; Hartwell, Kimberly A.; Chu, Lisa P.; Järås, Marcus LU ; Puram, Rishi V.; Puissant, Alexandre; Callahan, Kevin P.; Ashton, John and McConkey, Marie E., et al. (2013) In Cancer Cell 24(1). p.45-58
Abstract

We used an invivo 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 invivo 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... (More)

We used an invivo 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 invivo 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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@article{b6f2a224-8912-48a0-af07-7e82adf73e99,
  abstract     = {<p>We used an invivo 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 invivo 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.</p>},
  author       = {Miller, Peter G. and Al-Shahrour, Fatima and Hartwell, Kimberly A. and Chu, Lisa P. and Järås, Marcus and Puram, Rishi V. and Puissant, Alexandre and Callahan, Kevin P. and Ashton, John and McConkey, Marie E. and Poveromo, Luke P. and Cowley, Glenn S. and Kharas, Michael G. and Labelle, Myriam and Shterental, Sebastian and Fujisaki, Joji and Silberstein, Lev and Alexe, Gabriela and Al-Hajj, Muhammad A. and Shelton, Christopher A. and Armstrong, Scott A. and Root, David E. and Scadden, David T and Hynes, Richard O. and Mukherjee, Siddhartha and Stegmaier, Kimberly and Jordan, Craig T. and Ebert, Benjamin L.},
  issn         = {1535-6108},
  language     = {eng},
  month        = {07},
  number       = {1},
  pages        = {45--58},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {InVivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling},
  url          = {http://dx.doi.org/},
  volume       = {24},
  year         = {2013},
}