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

被引：137

作者：

Miller, Peter G. ^{[1
,2
]}

Al-Shahrour, Fatima ^{[1
,5
,6
]}

Hartwell, Kimberly A. ^{[5
,6
]}

Chu, Lisa P. ^{[1
]}

Jaeras, Marcus ^{[1
]}

Puram, Rishi V. ^{[1
]}

Puissant, Alexandre ^{[3
,4
]}

Callahan, Kevin P. ^{[7
]}

Ashton, John ^{[7
]}

McConkey, Marie E. ^{[1
]}

Poveromo, Luke P. ^{[1
]}

Cowley, Glenn S. ^{[5
,6
]}

Kharas, Michael G. ^{[8
,9
]}

Labelle, Myriam ^{[11
,12
]}

Shterental, Sebastian ^{[1
]}

Fujisaki, Joji ^{[13
,14
,15
,16
]}

Silberstein, Lev ^{[13
,14
,17
]}

Alexe, Gabriela ^{[3
,4
]}

Al-Hajj, Muhammad A. ^{[18
]}

Shelton, Christopher A. ^{[18
]}

Armstrong, Scott A. ^{[10
]}

Root, David E. ^{[5
,6
]}

Scadden, David T. ^{[13
,14
,17
]}

Hynes, Richard O. ^{[11
,12
,19
]}

Mukherjee, Siddhartha ^{[20
,21
]}

Stegmaier, Kimberly ^{[3
,4
,5
,6
]}

Jordan, Craig T. ^{[7
]}

Ebert, Benjamin L. ^{[1
,5
,6
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA

[5] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA

[6] MIT, Cambridge, MA 02142 USA

[7] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA

[8] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[9] Mem Sloan Kettering Canc Ctr, Ctr Cellular Engn, New York, NY 10065 USA

[10] Mem Sloan Kettering Canc Ctr, Mem Hosp Res Labs, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[11] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[12] MIT, Dept Biol, Cambridge, MA 02139 USA

[13] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[14] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[15] Massachusetts Gen Hosp, Ctr Syst Biol, Adv Microscopy Program, Boston, MA 02114 USA

[16] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA

[17] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[18] GlaxoSmithKline R&D, Oncol Unit, Collegeville, PA 19426 USA

[19] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[20] Columbia Univ, Sch Med, Dept Med, New York, NY 10032 USA

[21] Columbia Univ, Sch Med, Irving Canc Res Ctr, New York, NY 10032 USA

来源：

CANCER CELL | 2013年 / 24卷 / 01期

关键词：

ACUTE MYELOID-LEUKEMIA; STEM-CELLS; GLANZMANN THROMBASTHENIA; KINASE INHIBITOR; SYK; PROGENITOR; MICROENVIRONMENT; ESTABLISHMENT; PHAGOCYTOSIS; CHEMOTHERAPY;

D O I：

10.1016/j.ccr.2013.05.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 lntegrin 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.

引用

页码：45 / 58

页数：14

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