TY - JOUR
T1 - SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome
AU - Alachkar, Houda
AU - Santhanam, Ramasamy
AU - Maharry, Kati
AU - Metzeler, Klaus H.
AU - Huang, Xiaomeng
AU - Kohlschmidt, Jessica
AU - Mendler, Jason H.
AU - Benito, Juliana M.
AU - Hickey, Christopher
AU - Neviani, Paolo
AU - Dorrance, Adrienne M.
AU - Anghelina, Mirela
AU - Khalife, Jihane
AU - Tarighat, Somayeh S.
AU - Volinia, Stefano
AU - Whitman, Susan P.
AU - Paschka, Peter
AU - Hoellerbauer, Pia
AU - Wu, Yue Zhong
AU - Han, Lina
AU - Bolon, Brad N.
AU - Blum, William
AU - Mrózek, Krzysztof
AU - Carroll, Andrew J.
AU - Perrotti, Danilo
AU - Andreeff, Michael
AU - Caligiuri, Michael A.
AU - Konopleva, Marina
AU - Garzon, Ramiro
AU - Bloomfield, Clara D.
AU - Marcucci, Guido
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI70921
DO - 10.1172/JCI70921
M3 - Article
C2 - 24590286
AN - SCOPUS:84897555169
SN - 0021-9738
VL - 124
SP - 1512
EP - 1524
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -