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A Tumor Suppressor Function of LncRNA-X in Bcr-Abl-induced Tumorigenesis

ABSTRACT: Aberrant long noncoding RNA (lncRNA) expression has been described in many human malignancies, including leukemia. Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is a stem cell disease induced by Bcr-Abl hybrid gene. Here we attempt to identify lncRNAs associated with CML by analyzing lncRNA expression profiles in K562 cells when Bcr-Abl gene silenced. LncRNA microarray analysis revealed a group of lncRNAs that exhibit Bcr-Abl-dependent expression. In this study, we focused on lncRNA-X that was downregulated by Bcr-Abl, suggesting that lncRNA-X might have a function of tumor suppression. We showed that lncRNA-X over-expression delays Bcr-Abl-induced tumorigenesis in vivo, maybe through its effect on cell survival by modulating STAT5-dependent expression of anti-apoptotic Bcl-XL protein. We also demonstrated that lncRNA-X may affect tumor formation behavior of Bcr-Abl-transformed cells by regulating signaling pathways associated with leukemia stem cells of CML. Together, these results suggest that lncRNA-X suppresses Bcr-Abl-induced tumorigenesis, and the tumor suppressor function of lncRNA-X may be of significance for exploring novel therapeutic strategies for treating CML. This microarray was performed to identify lncRNAs associated with Bcr-Abl-induced chronic myeloid leukemia (CML).

ORGANISM(S): Homo sapiens

PROVIDER: GSE42269 | GEO | 2015/07/20

SECONDARY ACCESSION(S): PRJNA179508

REPOSITORIES: GEO

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Project description: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 ?-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. 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.

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A Tumor Suppressor Function of LncRNA-X in Bcr-Abl-induced Tumorigenesis

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