Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

POU4F1 is associated with t(8;21) AML and contributes directly to its unique transcriptional signature

ABSTRACT: POU4F1 is associated with t(8;21) acute myeloid leukemia (AML) and contributes directly to its unique transcriptional signature To identify targets of POU4F1, we performed gene expression profiling, comparing Pou4f1+/+ or Pou4f1-/- fetal liver cells to cells overexpressing POU4F1 and identified 140 differentially expressed genes.

ORGANISM(S): Mus musculus

SUBMITTER: Patrick Cahan

PROVIDER: E-GEOD-19997 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature.

Fortier J M JM Payton J E JE Cahan P P Ley T J TJ Walter M J MJ Graubert T A TA

Leukemia 20100408 5

The t(8;21)(q22;q22) translocation, present in approximately 5% of adult acute myeloid leukemia (AML) cases, produces the AML1/ETO (AE) fusion protein. Dysregulation of the Pit/Oct/Unc (POU) domain-containing transcription factor POU4F1 is a recurring abnormality in t(8;21) AML. In this study, we showed that POU4F1 overexpression is highly correlated with, but not caused by, AE. We observed that AE markedly increases the self-renewal capacity of myeloid progenitors from murine bone marrow or fet ...[more]

PMID: 20376082

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Project description: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). 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.

Dataset Information

POU4F1 is associated with t(8;21) AML and contributes directly to its unique transcriptional signature

Publications

POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature.

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