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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Apr 24, 2013 |
| Title |
In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Primary leukemia stem cells (LSCs) reside in an in vivo microenvironment that supports the growth and survival of malignant cells. We used an in vivo short hairpin RNA (shRNA) screening approach to identify novel genes that are essential for primary murine MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is selectively 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. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation in long term transplantation assays. We explored the signaling pathways downstream of Itgb3 using an additional in vivo shRNA screen and identified Syk as a critical mediator of Itgb3 activity in leukemia. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using the Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML, and demonstrate the utility of in vivo RNA interference screens.
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| Overall design |
We examined the effect of Itgb3 knockdown by gene expression profiling in primary leukemia cells.
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| Contributor(s) |
Miller 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, Al-Hajj MA, Shelton CA, Armstrong SA, Root DE, Scadden DT, Hynes RO, Mukherjee S, Stegmaier K, Jordan CT, Ebert BL |
| Citation(s) |
23770013 |
| Submission date |
Apr 23, 2013 |
| Last update date |
Jan 16, 2019 |
| Contact name |
Fatima Al-Shahrour |
| E-mail(s) |
shahrour@broadinstitute.org
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| Organization name |
Broad Institute of MIT and Harvard
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| Department |
Cancer program
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| Street address |
7 Cambridge Center
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL6887 |
Illumina MouseWG-6 v2.0 expression beadchip |
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| Samples (8)
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| GSM1128517 |
Itgb3 knockdown (Itgb3-17 shRNA) in LSCs, rep1 |
| GSM1128518 |
Itgb3 knockdown (Itgb3-17 shRNA) in LSCs, rep2 |
| GSM1128519 |
Itgb3 knockdown (Itgb3-17 shRNA) in LSCs, rep3 |
| GSM1128520 |
Itgb3 knockdown (Itgb3-20 shRNA) in LSCs, rep4 |
| GSM1128521 |
Itgb3 knockdown (Itgb3-20 shRNA) in LSCs, rep5 |
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| Relations |
| BioProject |
PRJNA198715 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE46307_RAW.tar |
15.8 Mb |
(http)(custom) |
TAR |
| GSE46307_non-normalized.txt.gz |
2.4 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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