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SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2014 Apr; Vol. 124 (4), pp. 1512-24. Date of Electronic Publication: 2014 Mar 03. - Publication Year :
- 2014
-
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.
- Subjects :
- Adolescent
Adult
Animals
Cell Line, Tumor
Cell Proliferation
Female
Gene Knockdown Techniques
Heterografts
Humans
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute pathology
Male
Mice
Mice, Inbred NOD
Mice, SCID
MicroRNAs genetics
MicroRNAs metabolism
Middle Aged
NF-kappa B metabolism
Nucleophosmin
Osteonectin antagonists & inhibitors
Osteonectin genetics
Prognosis
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
Sp1 Transcription Factor metabolism
Young Adult
beta Catenin metabolism
Leukemia, Myeloid, Acute etiology
Osteonectin physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 124
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 24590286
- Full Text :
- https://doi.org/10.1172/JCI70921