Gene Expression-Based High Throughput Screening (GE-HTS) and Application to Leukemia Differentiation

Nature Genetics, Vol. 36, No. 3, 257-263, March 2004.. Published: 2004.02.07

Kimberly Stegmaier, Kenneth N. Ross, Sierra A. Colavito, Shawn O'Malley, Brent R. Stockwell, and Todd R. Golub

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Abstract

Chemical genomics involves generating large collections of small molecules and using them to modulate cellular states. Although there has been recent progress in the systematic synthesis of structurally diverse compounds, their use in screens of cellular circuitry has remained an ad hoc process. Here, we outline a general, efficient approach called GE-HTS (Gene Expression-Based High Throughput Screening) in which a gene expression signature is used as a surrogate for cellular states, and we describe its application in a particular setting -- the identification of compounds inducing the differentiation of acute myeloid leukemia cells. In screening 1,739 compounds, we identified 8 that reliably induced the differentiation signature, and furthermore yielded functional evidence of bona fide differentiation. The results indicate that GE-HTS may provide a powerful, general approach for chemical screening.

Keywords: AML cancer chemical genomics leukemia small molecule library screen

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Supplemental Data

Description Link/Filename
Text file describing supplemental information contents README
Manuscript ng1305.pdf
Manuscript Figure 1 Fig1_edited.pdf
Manuscript Figure 2 Fig2_edited.pdf
Manuscript Figure 3 Fig3_edited.pdf
Manuscript Figure 4 Fig4_edited.pdf
Manuscript Figure 5 Fig5_edited.pdf
Supplemental Information Document Stegmaier_SupplementaryMethodsFiguresTables.pdf
Supplemental Information Excel Worksheets Stegmaier_SupplementaryData.xls
Initial Myeloid Primary Cell Data Myeloid_primarycells.res
Initial HL-60 Cell Data HL60_undiff_PMA_ATRA.res
Compound Treated HL-60 Cell Data Myeloid_Screen_Compound_Eval.res
Primary Patient APL Cell Data Myeloid_APL_compound_eval.res
Initial Myeloid Primary Cell Data CEL Files Myeloid_primarycells_CELfiles.tar.gz
Initial HL-60 Cell Data CEL Files HL60_undiff_PMA_ATRA_CELfiles.tar.gz
Compound Treated HL-60 Cell Data CEL Files Myeloid_Screen_Compound_Eval_CELfiles.tar.gz
Primary Patient APL Cell Data CEL Files Myeloid_APL_compound_eval_CELfiles.tar.gz
Nature Genetics GE-HTS News and Views GE-HTS_NandV.pdf