Prognostic significance of osteopontin in acute myeloid leukemia: A meta‑analysis

Chen, Yong‐Bing; Ren, Shiquan; Li, Si‐Dan; Du, Zhongli

doi:10.3892/mco.2017.1302

Cited by 10 publications

(13 citation statements)

References 24 publications

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“…However levels (even though significantly upregulated) were low and attempts at protein detection in the model were unreliable. A meta-analysis of several studies indicates that serum osteopontin (OPN) is a marker of poor survival and a potential therapeutic target in AML patients [ 19 ]. We therefore looked for the presence of osteopontin in primary AML patient material.…”

Section: Resultsmentioning

confidence: 99%

A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

et al. 2017

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Dormant leukaemia initiating cells in the bone marrow niche are a crucial therapeutic target for total eradication of acute myeloid leukaemia. To study this cellular subset we created and validated an in vitro model employing the cell line TF-1a, treated with Transforming Growth Factor β1 (TGFβ1) and a mammalian target of rapamycin inhibitor. The treated cells showed decreases in total RNA, Ki-67 and CD71, increased aldehyde dehydrogenase activity, forkhead box 03A (FOX03A) nuclear translocation and growth inhibition, with no evidence of apoptosis or differentiation. Using human genome gene expression profiling we identified a signature enriched for genes involved in adhesion, stemness/inhibition of differentiation and tumour suppression as well as canonical cell cycle regulation. The most upregulated gene was the osteopontin-coding gene SPP1. Dormant cells also demonstrated significantly upregulated beta 3 integrin (ITGB3) and CD44, as well as increased adhesion to their ligands vitronectin and hyaluronic acid as well as to bone marrow stromal cells. Immunocytochemistry of bone marrow biopsies of AML patients confirmed the positive expression of osteopontin in blasts near the para-trabecular bone marrow, whereas osteopontin was rarely detected in mononuclear cell isolates. Unsupervised hierarchical clustering of the dormancy gene signature in primary acute myeloid leukaemia samples from the Cancer Genome Atlas identified a cluster enriched for dormancy genes associated with poor overall survival.

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Section: Resultsmentioning

confidence: 99%

A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

et al. 2017

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“…Both β3 integrins belong to the subgroup of RGD binding integrins, i.e., integrins recognizing ligands containing an RGD tripeptide sequence. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix and soluble vascular ligands [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Important ligands for the β3 integrins are given in Table 1 .…”

Section: The Promiscuity Of β3 Integrin Ligand Bindingmentioning

confidence: 99%

The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

Johansen

Brenner

Bartaula-Brevik

et al. 2018

IJMS

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Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two β3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and β3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, β3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The β3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased β3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of β2 integrins. Finally, high integrin αV/β3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of β3 integrins for leukemogenesis and chemosensitivity in AML.

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“…Opn is suggested to promote leukemic stem cell quiescence, homing and adhesion to the BM niche through CD44 expression providing protective ME to AML cells and inducing their chemoresistance . Clinically, it has been reported that Opn serum levels inversely correlate with AML prognosis . Our unique ex‐vivo POS system has provided a direct proof for an aberrant function of AML stroma, characterized by a high baseline Opn level which further rises in the presence of AML cells, supporting their proliferation.…”

Section: Discussionmentioning

confidence: 74%

“…As a glycoprotein secreted by osteoblasts and hematopoietic cells, Opn is known to suppress the proliferation of HSCs in vitro , thus regulating their pool. It is mainly expressed in the endosteal bone surface niche and adheres to hematopoietic progenitors through beta‐1 integrin . Constitutive activation of the GM‐CSF receptor has been found to be associated with increased Opn expression, which may lead to dysregulation of normal hematopoiesis, eventually causing AML development via a yet unknown mechanism.…”

Section: Discussionmentioning

confidence: 99%

Abnormal morphological and functional nature of bone marrow stromal cells provides preferential support for survival of acute myeloid leukemia cells

Yehudai‐Resheff

Attias‐Turgeman

Sabbah

et al. 2018

Intl Journal of Cancer

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Hematopoietic progenitors, residing in the bone marrow (BM) niche, are supported by mesenchymal stromal cells (MSCs). Cytogenetic and molecular aberrations in these progenitors lead to acute myeloid leukemia (AML). The BM-MSC role in leukemogenesis is not fully elucidated. In the current study, an ex-vivo system of patient's own stroma (POS), best mimicking the in-vivo BM niche, has been developed aiming to unravel interactions and crosstalk between MSCs and AML cells.POS derived from AML patients at diagnosis (Dx), relapse (Rx) and remission (Rm) was compared to healthy donor MSCs in terms of their morphology, growth pattern, support of leukemia cell viability and cytokine profile. Compared to control MSCs, POS (Dx/Rx, Rm) demonstrated a reduced proliferation rate (35%), significantly slower expansion, enlarged cell area (3-4-fold) and provided preferential support to leukemic cells of the same individual. Cytokine profiling showed significantly higher secreted phosphoprotein-1 (SPP1) expression in Dx/Rx and Rm POS compared to healthy MSCs. Additionally, the angiopoietin-1 expression was elevated in Dx/Rx POS with a further increase in the AML cell presence. In conclusion, the fact that POS derived in active disease and remission exhibited similar morphological and functional characteristics, might imply the involvement of the BM niche in leukemogenesis.

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Prognostic significance of osteopontin in acute myeloid leukemia: A meta‑analysis

Cited by 10 publications

References 24 publications

A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

Abnormal morphological and functional nature of bone marrow stromal cells provides preferential support for survival of acute myeloid leukemia cells

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