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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.

Detaljer

Författare
  • Peter G. Miller
  • Fatima Al-Shahrour
  • Kimberly A. Hartwell
  • Lisa P. Chu
  • Rishi V. Puram
  • Alexandre Puissant
  • Kevin P. Callahan
  • John Ashton
  • Marie E. McConkey
  • Luke P. Poveromo
  • Glenn S. Cowley
  • Michael G. Kharas
  • Myriam Labelle
  • Sebastian Shterental
  • Joji Fujisaki
  • Lev Silberstein
  • Gabriela Alexe
  • Muhammad A. Al-Hajj
  • Christopher A. Shelton
  • Scott A. Armstrong
  • David E. Root
  • David T Scadden
  • Richard O. Hynes
  • Siddhartha Mukherjee
  • Kimberly Stegmaier
  • Craig T. Jordan
  • Benjamin L. Ebert
Externa organisationer
  • Brigham and Women's Hospital / Harvard Medical School
  • Harvard Medical School
  • Massachusetts Institute of Technology
  • University of Rochester School of Medicine and Dentistry
  • Memorial Sloan-Kettering Cancer Center
  • Massachusetts General Hospital
  • Harvard Stem Cell Institute
  • SmithKline Beecham Pharmaceuticals
  • Howard Hughes Medical Institute
  • Columbia University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)45-58
Antal sidor14
TidskriftCancer Cell
Volym24
Utgivningsnummer1
StatusPublished - 2013 jul 8
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa