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Series GSE33892 Query DataSets for GSE33892
Status Public on Nov 24, 2011
Title Comparison of TEX and M9-ENL1 cell lines to HL60 and THP1 cell lines
Organism Homo sapiens
Experiment type Third-party reanalysis
Expression profiling by array
Summary Gene regulatory networks that govern hematopoietic stem cells (HSC) and leukemia–initiating cells (L-IC) are deeply entangled. Thus, the discovery of compounds that target L-IC while sparing HSC is an attractive but difficult endeavor. Presently, most drug discovery approaches fail to counter-screen compounds against normal hematopoietic stem/progenitor cells (HSPC) to assess therapeutic index. Here, we present a combined in vitro and in vivo strategy to identify compounds specific to L-IC in acute myeloid leukemia (AML). A high-throughput screen of 4000 compounds on novel leukemia cell lines derived from human experimental leukemogenesis models yielded 80 hits, of which most were toxic to normal HSPC. Of the 10 compounds that passed this initial filter, we chose to characterize a single compound, kinetic riboside (KR), on AML L-IC and HSPC. KR demonstrated comparable efficacy to standard therapies against 63 primary AMLs. In vitro, KR effectively targeted the L-IC-enriched CD34+CD38- AML fraction, while sparing normal HSPC enriched fractions, although these effects were mitigated on HSC assayed in vivo, and highlights the importance of in vivo L-IC and HSC assays to measure function. Overall, we provide a novel approach to screen large drug libraries for the discovery of anti-L-IC compounds for human leukemias.

The gene expression profile of TEX and M9-ENL1 cells were compared to HL-60 (Series GSE16160, GSE28185) and THP1 (Series GSE28185), to determine if TEX and M9-ENL1 cells were more enriched in stem cell (embryonic, adult, leukemia, and cancer) gene sets using Gene Set Enrichment Analysis (GSEA).
Overall design TEX and M9-ENL1 cells were treated with DMSO in triplicate. Total RNA was harvested and analyzed with the Affymetrix Human Genome U133A 2.0 Array. Raw data was background corrected with RMA, normalized using quantiles method, corrected using only PM values, and median polished to generate log2 values. Published HL-60 and THP-1 raw data using the same Affymetrix array were processed identically. To account for batch variation, the log2 values were adjusted using ComBat in GenePattern with a parametric Empirical Bayes priors distribution estimation method and without covariate analysis.
Contributor(s) Eppert K, McDermott SP, Dick JE
Citation(s) 22160482
Submission date Nov 22, 2011
Last update date Dec 06, 2018
Contact name Kolja Eppert
Organization name University Health Network
Street address 101 College St., rm 8-301
City Toronto
State/province Ontario
ZIP/Postal code M5G 1L7
Country Canada
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (12)
GSM838425 TEX, triplicate 1
GSM838426 TEX, triplicate 2
GSM838427 TEX, triplicate 3
BioProject PRJNA148329

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE33892_RAW.tar 23.8 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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