Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA399109 | ENA |
REPOSITORIES: ENA
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Project description:The family of signal transduction adapter proteins (STAPs) has been reported to be involved in a variety of intracellular signaling and transcriptional molecules. We originally cloned STAP-2 as a c-fms interacting protein and found the effects on chronic myeloid leukemia (CML) leukemogenesis. STAP-2 binds to BCR-ABL, up-regulates BCR-ABL phosphorylation and activates its downstream molecules. In this study, we evaluated the role of STAP-1, another member of the family, in CML pathogenesis. The expression of human STAP-1 is aberrantly upregulated in CML stem cells (LSCs) in patient bone marrow. Using experimental model mice, we revealed that deletion of STAP-1 prolonged survival of CML mice with the induced apoptosis of LSCs. The impaired phosphorylated status of STAT5 by STAP-1 ablation results in downregulation of anti-apoptotic genes, BCL-2 and BCL-xL. Interestingly, transcriptome analyses indicate that STAP-1 affects several signaling pathways related to BCR-ABL, JAK2 as well as PPARγ. This adaptor protein directly binds not only BCR-ABL, also STAT5 proteins, showing synergistic effects of STAP-1 inhibition on the treatment with BCR-ABL or JAK2 tyrosine kinase inhibitor. It is known that the inhibition of BCR-ABL alone cannot eliminate CML LSCs. Our results have identified STAP-1 as a regulator of CML LSCs and support the evidence as a novel therapeutic target for CML cure.
2020-07-15 | GSE127984 | GEO
Project description: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).
2015-07-20 | GSE42269 | GEO
Project description:Gene expression profiling in BCR/ABL expressing LSCs and BCR/ABL expressing Alox5-/-LSCs
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Project description:Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to completely eradicate Bcr-Abl+ leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl+ leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib in CML cells. This screen identified numerous components of a Wnt/Ca2+/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl+ acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl+ leukemias.
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