SPARC is dispensable for murine hematopoiesis, despite its suspected pathophysiological role in 5q-myelodysplastic syndrome

Siva, Kavitha; Jaako, Pekka; Miharada, Kenichi; Rörby, Emma; Ehinger, Mats; Karlsson, Göran; Karlsson, Stefán

doi:10.1038/leu.2012.97

Cited by 18 publications

(17 citation statements)

References 15 publications

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“…Although this suggests that SPARC expression is a treatment-response predictor and perhaps plays a role in normal hematopoiesis, to date, no biological evidence supporting this notion has been reported. Indeed, SPARC was found to be dispensable for murine hematopoiesis (59). Nevertheless, the complexity of the hematopoietic role of SPARC is illustrated by a recent report (60).…”

Section: Discussionmentioning

confidence: 99%

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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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 integrinlinked 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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Section: Discussionmentioning

confidence: 99%

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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“…The myeloproliferative phenotype of Apc min Ͼ Sparc Ϫ/Ϫ chimeras consisted of BM hypergranulopoiesis with increased numbers of circulating mature granulocytes and myeloid precursors and was not observed in Apc min Ͼ WT chimeras, further indicating that SPARC deficiency in the BM stroma may represent a condition favoring myeloid expansion under a myeloproliferative stress. Recently, Siva et al have reported that SPARC is dispensable for murine hematopoiesis both at the steady state and under the stress induced by acute hemolysis or BM transplantation, 50 suggesting that SPARC deficiency does not alter the hematopoietic potential of the BM and that its contribution to the 5qϪ MDS phenotype may be subordinated to that of other molecular events that are not recapitulated in Sparc Ϫ/Ϫ models. We obtained similar results in the BM transplantion setting, in which Sparc Ϫ/Ϫ recipients were reconstituted without difference from WT recipients, even in the presence of low numbers of donor Lin Ϫ cells (ie, 2 ϫ 10 3 cells, data not shown).…”

Section: Discussionmentioning

confidence: 99%

Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion

Tripodo

Sangaletti

Guarnotta

et al. 2012

Blood

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In myeloid malignancies, the neoplastic clone outgrows normal hematopoietic cells toward BM failure. This event is also sustained by detrimental stromal changes, such as BM fibrosis and osteosclerosis, whose occurrence is harbinger of a dismal prognosis. We show that the matricellular protein SPARC contributes to the BM stromal response to myeloproliferation. The degree of SPARC expression in BM stromal elements, including CD146 ؉ mesenchymal stromal cells, correlates with the degree of stromal changes, and the sever-

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“…10 SPARC has attracted attention in the hematopoietic research field, as it is part of the commonly deleted region of the 5q myelodysplastic syndrome and is deregulated in other hematologic malignancies. [11][12][13][14][15] However, previous studies have only demonstrated a role for SPARC in erythroid development. For instance, a reduction of burst-forming units of the erythroid lineage (BFU-E) was detected in SPARC-deficient bone marrow (BM), although erythrocyte and erythroid progenitor numbers were normal in vivo.…”

Section: Introductionmentioning

confidence: 96%

“…For instance, a reduction of burst-forming units of the erythroid lineage (BFU-E) was detected in SPARC-deficient bone marrow (BM), although erythrocyte and erythroid progenitor numbers were normal in vivo. [11][12][13][14][15] There is experimental evidence that SPARC promotes the development of erythroid progenitors in a non-cell autonomous fashion, as the BFU-E defect could be rescued by exogenous SPARC. 12 The role of SPARC in HSC biology remains poorly understood, although a recent study suggests that SPARC is dispensable for murine HSC function.…”

Section: Introductionmentioning

confidence: 99%

“…12 The role of SPARC in HSC biology remains poorly understood, although a recent study suggests that SPARC is dispensable for murine HSC function. 13 SPARC is part of the BM niche and a critical regulator of bone remodeling. 16 As SPARC is expressed in remodeling tissues and during tissue repair, some phenotypes of mutant mice may only become obvious in situations of injury.…”

Section: Introductionmentioning

confidence: 99%

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