{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Alachkar H"],"funding":["NCI NIH HHS"],"pagination":["1512-24"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3973087"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["124(4)"],"pubmed_abstract":["Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML."],"journal":["The Journal of clinical investigation"],"pubmed_title":["SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome."],"pmcid":["PMC3973087"],"funding_grant_id":["CA55164","CA016058","CA101140","P30 CA016058","CA140158","U10 CA077658","U10 CA180882","P30 CA016672","U10 CA101140","U10 CA180861","CA77658","R01 CA095512","U24 CA196171","U10 CA180821","P50 CA100632","P01 CA055164","CA100632","P50 CA140158"],"pubmed_authors":["Benito JM","Hoellerbauer P","Mendler JH","Neviani P","Whitman SP","Han L","Andreeff M","Santhanam R","Volinia S","Mrozek K","Paschka P","Perrotti D","Metzeler KH","Bolon BN","Bloomfield CD","Marcucci G","Alachkar H","Maharry K","Hickey C","Anghelina M","Khalife J","Garzon R","Tarighat SS","Blum W","Konopleva M","Huang X","Carroll AJ","Kohlschmidt J","Dorrance AM","Wu YZ","Caligiuri MA"],"additional_accession":[]},"is_claimable":false,"name":"SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome.","description":"Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML.","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Apr","modification":"2025-04-20T02:46:07.969Z","creation":"2019-03-27T01:24:18Z"},"accession":"S-EPMC3973087","cross_references":{"pubmed":["24590286"],"doi":["10.1172/JCI70921","10.1172/jci70921"]}}