title: 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.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Miller
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hartwell
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Chu
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.forename: Rishi V
authors.initials: RV
authors.lastname: Puram
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Callahan
authors.forename: John
authors.initials: J
authors.lastname: Ashton
authors.forename: Marie E
authors.initials: ME
authors.lastname: McConkey
authors.forename: Luke P
authors.initials: LP
authors.lastname: Poveromo
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.forename: Myriam
authors.initials: M
authors.lastname: Labelle
authors.forename: Sebastian
authors.initials: S
authors.lastname: Shterental
authors.forename: Joji
authors.initials: J
authors.lastname: Fujisaki
authors.forename: Lev
authors.initials: L
authors.lastname: Silberstein
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Al-Hajj
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Shelton
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000818:Animals; D001483:Base Sequence; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: C495270:CTNNB1 protein, human; C061248:ITGB3 protein, human; D039661:Integrin beta3; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D051176:beta Catenin; D051788:Myeloid-Lymphoid Leukemia Protein