SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome.
Alachkar H, Santhanam R, Maharry K, Metzeler KH, Huang X, Kohlschmidt J, Mendler JH, Benito JM, Hickey C, Neviani P, Dorrance AM, Anghelina M, Khalife J, Tarighat SS, Volinia S, Whitman SP, Paschka P, Hoellerbauer P, Wu YZ, Han L, Bolon BN, Blum W, Mrózek K, Carroll AJ, Perrotti D, Andreeff M, Caligiuri MA, Konopleva M, Garzon R, Bloomfield CD, Marcucci G
J Clin Invest 124 1512-24 04/01/2014
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-?B transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent ß-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-?B 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.Full Text