Dataset Information


Gene expression profiling in BCR/ABL expressing LSCs and BCR/ABL expressing Alox5-/-LSCs

ABSTRACT: We previously demonstrated that Alox5 deficiency impairs the function of LSCs and prevents the initiation of BCR-ABL-induced CML. To identify the pathways in which Alox5 gene regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to further dissect this pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs derived from our mouse model for BCR-ABL-induced CML. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was up-regulated in Alox5-/- LSCs, suggesting that Msr1 might suppress the proliferation of LSCs.  Using our CML mouse model, we show that Msr1 is down-regulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and β-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of Msr1 function may be of significance in the development of novel therapeutic strategies targeting CML. Overall design: To identify genes that are regulated by BCR-ABL in LSCs and LSCs without Alox5 gene, we compared the gene profile between wild type(WT) LSCs or Alox5-/- LSCs.

INSTRUMENT(S): [MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version]

ORGANISM(S): Mus musculus  

SUBMITTER: shaoguang Li  

PROVIDER: GSE29347 | GEO | 2011-05-17



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