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Cancer Cell DOI:10.1016/j.ccr.2013.05.004

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

Publication TypeJournal Article
Year of Publication2013
AuthorsMiller, PG, Al-Shahrour, F, Hartwell, KA, Chu, LP, Järås, M, Puram, RV, Puissant, A, Callahan, KP, Ashton, J, McConkey, ME, Poveromo, LP, Cowley, GS, Kharas, MG, Labelle, M, Shterental, S, Fujisaki, J, Silberstein, L, Alexe, G, Al-Hajj, MA, Shelton, CA, Armstrong, SA, Root, DE, Scadden, DT, Hynes, RO, Mukherjee, S, Stegmaier, K, Jordan, CT, Ebert, BL
JournalCancer Cell
Volume24
Issue1
Pages45-58
Date Published2013 Jul 08
ISSN1878-3686
KeywordsAnimals, Base Sequence, beta Catenin, Hematopoietic Stem Cells, Humans, Integrin beta3, Leukemia, Myeloid, Acute, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, RNA Interference, RNA, Small Interfering, Signal Transduction
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1535-6108(13)00197-9
DOI10.1016/j.ccr.2013.05.004
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23770013?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID23770013
PubMed Central IDPMC3746037
Grant ListR01 HL082945 / HL / NHLBI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
U54 CA163109 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
RC1 CA145229 / CA / NCI NIH HHS / United States
R01 CA140292 / CA / NCI NIH HHS / United States