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

Cancer Cell. 2013 Jul 8;24(1):45-58. doi: 10.1016/j.ccr.2013.05.004. Epub 2013 Jun 13.

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.

MeSH terms

  • Animals
  • Base Sequence
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Integrin beta3 / genetics
  • Integrin beta3 / physiology*
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Oncogene Proteins, Fusion / genetics
  • RNA Interference*
  • RNA, Small Interfering / genetics
  • Signal Transduction / physiology*
  • beta Catenin / physiology

Substances

  • CTNNB1 protein, human
  • ITGB3 protein, human
  • Integrin beta3
  • MLL-AF9 fusion protein, human
  • Oncogene Proteins, Fusion
  • RNA, Small Interfering
  • beta Catenin
  • Myeloid-Lymphoid Leukemia Protein

Associated data

  • GENBANK/GSE46302
  • GENBANK/GSE46307