title: SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome.
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.
authors.forename: Houda
authors.initials: H
authors.lastname: Alachkar
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Huang
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.forename: Jason H
authors.initials: JH
authors.lastname: Mendler
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Benito
authors.forename: Christopher
authors.initials: C
authors.lastname: Hickey
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: Mirela
authors.initials: M
authors.lastname: Anghelina
authors.forename: Jihane
authors.initials: J
authors.lastname: Khalife
authors.forename: Somayeh S
authors.initials: SS
authors.lastname: Tarighat
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Pia
authors.initials: P
authors.lastname: Hoellerbauer
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Lina
authors.initials: L
authors.lastname: Han
authors.forename: Brad N
authors.initials: BN
authors.lastname: Bolon
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D000090243:Nucleophosmin; D015676:Osteonectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D000090243:Nucleophosmin; D015676:Osteonectin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016329:Sp1 Transcription Factor; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C495270:CTNNB1 protein, human; C532045:MIRN29a microRNA, human; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; C577241:SPARC protein, human