scholarly journals The human homologue of rat NG2, a chondroitin sulfate proteoglycan, is not expressed on the cell surface of normal hematopoietic cells but is expressed by acute myeloid leukemia blasts from poor-prognosis patients with abnormalities of chromosome band 11q23

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1123-1133 ◽  
Author(s):  
FO Smith ◽  
C Rauch ◽  
DE Williams ◽  
CJ March ◽  
D Arthur ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Hematopoietic Cells ◽  
Chondroitin Sulfate Proteoglycan ◽  
Chromosome Band ◽  
Sulfate Proteoglycan ◽  
Acute Myeloid

In our efforts to produce monoclonal antibodies that recognize cell- surface antigens expressed by hematopoietic precursor and stromal cells, we generated a monoclonal antibody, 7.1, which recognizes a 220- to 240-kD cell-surface protein whose N-terminal amino acid sequence is identical to the rat NG2 chondroitin sulfate proteoglycan molecule. This chondroitin sulfate proteoglycan, previously reported to be expressed by human melanoma cells, was not found to be expressed by normal hematopoietic cells, nor was it expressed on the cell surface of cell lines of hematopoietic origin including cell lines with 11q23 abnormalities. It was found on the cell surface of acute myeloid leukemia (AML) blasts and cell lines derived from nonhematopoietic tissues. Samples of leukemic marrow from 166 children with AML enrolled on Childrens Cancer Group protocol 213 were evaluated for cell-surface expression of this proteoglycan molecule. In 18 of 166 (11%) patient samples, greater than 25% of leukemic blasts expressed the NG2 molecule. These 18 patients had a poorer outcome with respect to survival (P = .002) and event-free survival (P = .035) with an actuarial survival at 4 years of 16.7%. Blast cell expression of the NG2 molecule was strongly associated with French-American-British M5 morphology (P < .0001) and abnormalities in chromosome band 11q23, site of the MLL gene. These results show that the NG2 molecule is expressed by malignant hematopoietic cells that have abnormalities in chromosome band 11q23, suggesting that antibody 7.1 may be useful in the rapid identification of this group of poor-prognosis patients.

scholarly journals Interaction of the NG2 chondroitin sulfate proteoglycan with type VI collagen.

1990 ◽  
Vol 111 (6) ◽  
pp. 3177-3188 ◽  
Author(s):  
W B Stallcup ◽  
K Dahlin ◽  
P Healy
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Cell Lines ◽  
Intervertebral Discs ◽  
Chondroitin Sulfate Proteoglycan ◽  
Cellular Interactions ◽  
Sulfate Proteoglycan ◽  
Type Vi Collagen ◽  
Double Labeling ◽  
Parallel Change

The NG2 chondroitin sulfate proteoglycan is a membrane-associated molecule of approximately 500 kD with a core glycoprotein of 300 kD. Both the complete proteoglycan and a smaller quantity of the 300-kD core are immunoprecipitable with polyclonal and monoclonal antibodies against purified NG2. From some cell lines, the antibodies coprecipitate NG2 and type VI collagen, the latter appearing on SDS-PAGE as components of 140 and 250 kD under reducing conditions. The immunoprecipitation of type VI collagen does not seem to be due to recognition of the collagen by the antibodies, but rather to binding of the collagen to NG2. Studies on the NG2-type VI collagen complex suggest that binding between the two molecules is mediated by protein-protein interactions rather than by ionic interactions involving the glycosaminoglycans. Immunofluorescence double labeling in frozen sections of embryonic rat shows that NG2 and type VI collagen are colocalized in structures such as the intervertebral discs and arteries of the spinal column. In vitro the two molecules are highly colocalized on the surface of several cell lines. Treatment of these cells resulting in a change in the distribution of NG2 on the cell surface also causes a parallel change in type VI collagen distribution. Our results suggest that cell surface NG2 may mediate cellular interactions with the extracellular matrix by binding to type VI collagen.

scholarly journals Brevican, a Chondroitin Sulfate Proteoglycan of Rat Brain, Occurs as Secreted and Cell Surface Glycosylphosphatidylinositol-anchored Isoforms

1995 ◽  
Vol 270 (45) ◽  
pp. 27206-27212 ◽  
Author(s):  
Constanze I. Seidenbecher ◽  
Karin Richter ◽  
Uwe Rauch ◽  
Reinhard Fässler ◽  
Craig C. Garner ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Rat Brain ◽  
Chondroitin Sulfate Proteoglycan ◽  
Sulfate Proteoglycan

scholarly journals High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
François Hermetet ◽  
Rony Mshaik ◽  
John Simonet ◽  
Patrick Callier ◽  
Laurent Delva ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Cell Surface ◽  
High Fat Diet ◽  
Myeloid Leukemia ◽  
Potent Inhibitor ◽  
Hematopoietic Cells ◽  
High Fat ◽  
Stat3 Signaling ◽  
Acute Myeloid

Abstract Using a MLL-AF9 knock-in mouse model, we discovered that consumption of a high-fat diet (HFD) accelerates the risk of developing acute myeloid leukemia (AML). This regimen increases the clusterization of FLT3 within lipid rafts on the cell surface of primitive hematopoietic cells, which overactivates this receptor as well as the downstream JAK/STAT signaling known to enhance the transformation of MLL-AF9 knock-in cells. Treatment of mice on a HFD with Quizartinib, a potent inhibitor of FLT3 phosphorylation, inhibits the JAK3/STAT3, signaling and finally antagonizes the accelerated development of AML that occurred following the HFD regimen. We can therefore conclude that, on a mouse model of AML, a HFD enforces the FLT3 signaling pathway on primitive hematopoietic cells and, in turn, improves the oncogenic transformation of MLL-AF9 knock-in cells and the leukemia initiation.

scholarly journals Codistribution of heparan sulfate proteoglycan, laminin, and fibronectin in the extracellular matrix of normal rat kidney cells and their coordinate absence in transformed cells.

1982 ◽  
Vol 94 (1) ◽  
pp. 28-35 ◽  
Author(s):  
E G Hayman ◽  
A Oldberg ◽  
G R Martin ◽  
E Ruoslahti
Keyword(s):  
Cell Surface ◽  
Heparan Sulfate ◽  
Chondroitin Sulfate ◽  
Rat Kidney ◽  
Heparan Sulfate Proteoglycan ◽  
Chondroitin Sulfate Proteoglycan ◽  
Transformed Cells ◽  
Kidney Cells ◽  
Sulfate Proteoglycan ◽  
Normal Rat

We used antibodies raised against both a heparan sulfate proteoglycan purified from a mouse sarcoma and a chondroitin sulfate proteoglycan purified from a rat yolk sac carcinoma to study the appearance and distribution of proteoglycans in cultured cells. Normal rat kidney cells displayed a fibrillar network of immunoreactive material at the cell surface when stained with antibodies to heparan sulfate proteoglycan, while virally transformed rat kidney cells lacked such a surface network. Antibodies to chondroitin sulfate proteoglycan revealed a punctate pattern on the surface of both cell types. The distribution of these two proteoglycans was compared to that of fibronectin by double-labeling immunofluorescent staining. The heparan sulfate proteoglycan was found to codistribute with fibronectin, and fibronectin and laminin gave coincidental stainings. The distribution of chondroitin sulfate proteoglycan was not coincidental with that of fibronectin. Distinct fibers containing fibronectin but lacking chondroitin sulfate proteoglycan were observed. When the transformed cells were cultured in the presence of sodium butyrate, their morphology changed, and fibronectin, laminin, and heparan sulfate proteoglycan appeared at the cell surface in a pattern resembling that of normal cells. These results suggest that fibronectin, laminin, and heparan sulfate proteoglycan may be complexed at the cell surface. The proteoglycan may play a central role in assembly of such complexes since heparan sulfate has been shown to interact with both fibronectin and laminin.

Inhibition Of LSD1 As a Therapeutic Strategy For The Treatment Of Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3964-3964 ◽  
Author(s):  
Ryan G. Kruger ◽  
Helai Mohammad ◽  
Kimberly Smitheman ◽  
Monica Cusan ◽  
Yan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Surface ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Stem Cell Differentiation ◽  
Ethical Review Process ◽  
Acute Myeloid

Abstract Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. These complexes include Histone Deacetylases (HDAC1/2) and Co-Repressor for Element-1-Silencing Transcription factor (CoREST). LSD1 mediated H3K4 demethylation can result in a repressive chromatin environment that silences gene expression. LSD1 has been shown to play a role in development in various contexts. LSD1 can interact with pluripotency factors in human embryonic stem cells and is important for decommissioning enhancers in stem cell differentiation. Beyond embryonic settings, LSD1 is also critical for hematopoietic differentiation. LSD1 is overexpressed in multiple cancer types and recent studies suggest inhibition of LSD1 reactivates the all-trans retinoic acid receptor pathway in acute myeloid leukemia (AML). These studies implicate LSD1 as a key regulator of the epigenome that modulates gene expression through post-translational modification of histones and through its presence in transcriptional complexes. The current study describes the anti-tumor effects of a novel LSD1 inhibitor (GSK2879552) in AML. GSK2879552 is a potent, selective, mechanism-based, irreversible inhibitor of LSD1. Screening of over 150 cancer cell lines revealed that AML cells have a unique requirement for LSD1. While LSD1 inhibition did not affect the global levels of H3K4me1 or H3K4me2, local changes in these histone marks were observed near transcriptional start sites of putative LSD1 target genes. This increase in the transcriptionally activating histone modification correlated with a dose dependent increase in gene expression. Treatment with GSK2879552 promoted the expression of cell surface markers, including CD11b and CD86, associated with a differentiated immunophenotype in 12 of 13 AML cell lines. For example, in SKM-1 cells, increases in cell surface expression of CD86 and CD11b occurred after as early as one day of treatment with EC50 values of 13 and 7 nM respectively. In a separate study using an MV-4-11 engraftment model, increases in CD86 and CD11b were observed as early as 8 hours post dosing. GSK2879552 treatment resulted in a potent anti-proliferative growth effect in 19 of 25 AML cell lines (average EC50 = 38 nM), representing a range of AML subtypes. Potent growth inhibition was also observed on AML blast colony forming ability in 4 out of 5 bone marrow samples derived from primary AML patient samples (average EC50 = 205 nM). The effects of LSD1 inhibition were further characterized in an in vivo mouse model of AML induced by transduction of mouse hematopoietic progenitor cells with a retrovirus encoding MLL-AF9 and GFP. Primary AML cells were transplanted into a cohort of secondary recipient mice and upon engraftment, the mice were treated for 17 days. After 17 days of treatment, control treated mice had 80% GFP+ cells in the bone marrow whereas treated mice possessed 2.8% GFP positive cells (p<0.012). The percentage of GFP+ cells continued to decrease to 1.8% by 1-week post therapy. Remarkably, in a preliminary assessment for survival, control-treated mice succumbed to AML by 28 days post transplant, while treated mice showed prolonged survival. Together, these data demonstrate that pharmacological inhibition of LSD1 may provide a promising treatment for AML by promoting differentiation and subsequent growth inhibition of AML blasts. GSK2879552 is currently in late preclinical development and clinical trials are anticipated to start in 2014. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Disclosures: Kruger: GlaxoSmithKline Pharmaceuticals: Employment. Mohammad:GlaxoSmithKline Pharmaceuticals: Employment. Smitheman:GlaxoSmithKline Pharmaceuticals: Employment. Liu:GlaxoSmithKline Pharmaceuticals: Employment. Pappalardi:GlaxoSmithKline Pharmaceuticals: Employment. Federowicz:GlaxoSmithKline Pharmaceuticals: Employment. Van Aller:GlaxoSmithKline Pharmaceuticals: Employment. Kasparec:GlaxoSmithKline Pharmaceuticals: Employment. Tian:GlaxoSmithKline Pharmaceuticals: Employment. Suarez:GlaxoSmithKline Pharmaceuticals: Employment. Rouse:GlaxoSmithKline Pharmaceuticals: Employment. Schneck:GlaxoSmithKline Pharmaceuticals: Employment. Carson:GlaxoSmithKline Pharmaceuticals: Employment. McDevitt:GlaxoSmithKline Pharmaceuticals: Employment. Ho:GlaxoSmithKline Pharmaceuticals: Employment. McHugh:GlaxoSmithKline Pharmaceuticals: Employment. Miller:GlaxoSmithKline Pharmaceuticals: Employment. Johnson:GlaxoSmithKline Pharmaceuticals: Employment. Armstrong:Epizyme Inc.: Has consulted for Epizyme Inc. Other. Tummino:GlaxoSmithKline Pharmaceuticals: Employment.

scholarly journals A Rapid Culture Technique Produces Functional Dendritic-Like Cells from Human Acute Myeloid Leukemia Cell Lines

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Jian Ning ◽  
David Morgan ◽  
Derwood Pamphilon
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Cell Surface ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Antigen Uptake ◽  
Human Acute Myeloid Leukemia ◽  
Ifn Γ ◽  
Acute Myeloid

Most anti-cancer immunotherapeutic strategies involving dendritic cells (DC) as vaccines rely upon the adoptive transfer of DC loaded with exogenous tumour-peptides. This study utilized human acute myeloid leukemia (AML) cells as progenitors from which functional dendritic-like antigen presenting cells (DLC) were generated, that constitutively express tumour antigens for recognition by CD8+T cells. DLC were generated from AML cell lines KG-1 and MUTZ-3 using rapid culture techniques and appropriate cytokines. DLC were evaluated for their cell-surface phenotype, antigen uptake and ability to stimulate allogeneic responder cell proliferation, and production of IFN-γ; compared with DC derived from normal human PBMC donors. KG-1 and MUTZ-3 DLC increased expression of CD80, CD83, CD86, and HLA-DR, and MUTZ-3 DLC downregulated CD14 and expressed CD1a. Importantly, both KG-1 and MUTZ-3-derived DLC promoted proliferation of allogeneic responder cells more efficiently than unmodified cells; neither cells incorporated FITC-labeled dextran, but both stimulated IFN-γ production from responding allogeneic CD8+T cells. Control DC produced from PBMC using the FastDC culture also expressed high levels of critical cell surface ligands and demonstrated good APC function. This paper indicates that functional DLC can be cultured from the AML cell lines KG-1 and MUTZ-3, and FastDC culture generates functional KG-1 DLC.

scholarly journals Chondroitin sulfate proteoglycan Windpipe modulates Hedgehog signaling in Drosophila

2018 ◽  
Author(s):  
Masahiko Takemura ◽  
Fredrik Noborn ◽  
Jonas Nilsson ◽  
Eriko Nakato ◽  
Tsu-Yi Su ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Hedgehog Signaling ◽  
Transmembrane Protein ◽  
Wing Disc ◽  
Chondroitin Sulfate Proteoglycan ◽  
Growth Factor Signaling ◽  
Sulfate Proteoglycan ◽  
Sugar Chain ◽  
Hh Signaling

AbstractProteoglycans, a class of carbohydrate-modified proteins, often modulate growth factor signaling on the cell surface. However, the molecular mechanism by which proteoglycans regulate signal transduction is largely unknown. In this study, using a recently-developed glycoproteomic method, we found that Windpipe (Wdp) is a novel chondroitin sulfate proteoglycan (CSPG) in Drosophila. Wdp is a single-pass transmembrane protein with leucin-rich repeat (LRR) motifs and bears three CS sugar chain attachment sites in the extracellular domain. Here we show that Wdp modulates the Hedgehog (Hh) pathway. Overexpression of wdp inhibits Hh signaling in the wing disc, which is dependent on its CS chains and the LRR motifs. Conversely, loss of wdp leads to the upregulation of Hh signaling. Furthermore, knockdown of wdp increase the cell surface accumulation of Smoothened (Smo), suggesting that Wdp inhibits Hh signaling by regulating Smo stability. Our study demonstrates a novel role of CSPG in regulating Hh signaling.

Chondroitin sulfate proteoglycan form of cellular and cell-surface Alzheimer amyloid precursor

1993 ◽  
Vol 154 (1-2) ◽  
pp. 121-124 ◽  
Author(s):  
Junichi Shioi ◽  
Lawrence M. Refolo ◽  
Spiros Efthimiopoulos ◽  
Nikolaos K. Robakis
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Chondroitin Sulfate Proteoglycan ◽  
Sulfate Proteoglycan
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