Unknown,Transcriptomics,Genomics,Proteomics

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Genomic analysis of xCT-mediated regulatory network: identification of novel targets against AIDS-associated lymphoma

ABSTRACT: Kaposiâs sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the genomic gene profile altered by SASP treatment within 3 KSHV+ PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further functionally validate 2 downstream candidates, OSGIN1 (Oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), their relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these xCT-regulated novel downstream genes may help devise promising therapeutic strategies against PEL and/or other AIDS-related lymphoma. 3 KSHV PEL cell lines were treated with xCT selective inhibitor Sulfasalazine (SASP) and the gene expression signature was compared to that of untreated cells

ORGANISM(S): Homo sapiens

SUBMITTER: Zhiqiang Qin

PROVIDER: E-GEOD-65418 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.

Dai Lu L Cao Yueyu Y Chen Yihan Y Kaleeba Johnan A R JA Zabaleta Jovanny J Qin Zhiqiang Z

Oncotarget 20150501 14

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through ...[more]

PMID: 25860939

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Project description:Background. B-Acute lymphoblastic leukemia (B-ALL) represents a hematologic malignancy with poor clinical outcome and low survival rates in adult patients. Only 61% of Colombian adult patients with ALL achieve complete remission and a median overall survival of less than 11.3 months and event-free survival of 7.34 months. Identification of prognostic factors is crucial for proper treatment strategies and optimal results of therapy. The goal of our study was to determine if gene expression signatures correlate with response to therapy and to evaluate the utility of these as prognostic tools for survival to better predict patient risk prior to therapy. Methods and findings. This study included 43 adult patients newly diagnosed with B-cell precursor or common B-ALL. Through microarray gene expression profiles, we identified 442 genes differentially expressed between 27 leukemia patients who responded or not to induction chemotherapeutic treatment. Hierarchical analysis with the 99 most differentially expressed genes between the two groups revealed 3 sets of patients that differed in their clinical characteristics, giving these genes high prognostic clinical outcome impact. We validated the expression of 7 genes by RT-PCR in 43 patients, and in addition to finding a correlation with gene expression profiles, we established correlations with good and poor prognosis from the time of diagnosis. Conclusions. Our study suggests that the response to induction treatment and clinical outcome of patients can be predicted from the onset of the disease and that gene expression profiles can be used to stratify patient risk adequately and accurately. The present study represents the first that shows that gene expression profiling could become a clinically relevant tool for stratification in the early course of disease of Colombian adults B-ALL. Stem cells from bone marrow samples from B-acute lymphoblastic leukemia (B-ALL) patients responding or not to the inductive therapy were isolated by sorting, and the gene expression was compared between the two groups. This submission includes samples from 27 B-ALL patients and 3 healthy individuals.

Dataset Information

Genomic analysis of xCT-mediated regulatory network: identification of novel targets against AIDS-associated lymphoma

Publications

Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.

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