Loss of RKIP is a frequent event in myeloid sarcoma and promotes leukemic tissue infiltration.
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ABSTRACT:
SUBMITTER: Caraffini V
PROVIDER: S-EPMC5824335 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC5024751 | biostudies-literature
Project description: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-?B transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent ?-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-?B 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.
| S-EPMC3973087 | biostudies-other
Project description:Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.
| S-EPMC3969866 | biostudies-literature
Project description:The BCR-ABL fusion oncoprotein accelerates differentiation and proliferation of myeloid cells during the chronic phase of chronic myeloid leukemia (CP-CML). Here, the role of CCAAT/enhancer binding protein ? (C/EBP?), a regulator for 'emergency granulopoiesis,' in the pathogenesis of CP-CML was examined. C/EBP? expression was upregulated in Lineage(-) CD34(+) CD38(-) hematopoietic stem cells (HSCs) and myeloid progenitors isolated from bone marrow of patients with CP-CML. In EML cells, a mouse HSC line, BCR-ABL upregulated C/EBP?, at least in part, through the activation of STAT5. Myeloid differentiation and proliferation induced by BCR-ABL was significantly impaired in C/EBP?-deficient bone marrow cells in vitro. Mice that were transplanted with BCR-ABL-transduced C/EBP? knockout bone marrow cells survived longer than mice that received BCR-ABL-transduced wild-type (WT) bone marrow cells. Significantly higher levels of leukemic stem cells were maintained in BCR-ABL-transduced C/EBP?-deficient cells than in BCR-ABL-transduced WT cells. These results suggest that C/EBP? is involved in BCR-ABL-mediated myeloid expansion. Further elucidation of the molecular mechanisms underlying the C/EBP?-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.
| S-EPMC4506742 | biostudies-literature
Project description:The aim of this study is to evaluate the frequency of CTNNA1 hypermethylation in acute myeloid leukemia (AML) patients in an attempt to improve molecular prognostic model. CTNNA1 promoter methylation levels in 319 newly diagnosed AML patients were detected using quantitative methylation-specific polymerase chain reaction (qMS-PCR). Furthermore, hematological characteristics, cytogenetic abnormalities, and genetic mutation status were analyzed, followed by assessment of clinical impact. Our findings demonstrated that CTNNA1 hypermethylation was observed in 25% AML patients. Hypermethylation of the CTNNA1 promoter was associated with unfavorable karyotype, and also possessed the higher frequency of coexisting with ASXL1 and RUNX1 mutations. Patients with CTNNA1 hypermethylation exhibited the shorter relapse-free survival (RFS) and overall survival (OS) in the whole AML and non-M3 AML patients. Moreover, patients with the higher methylation levels had more aggressive course than those with relative lower levels. In multivariate analyses, CTNNA1 hypermethylation was an independent factor predicting for poor RFS, but not for OS. In conclusion, CTNNA1 hypermethylation may be a reliable factor for improving prognostic molecular model for AML.
| S-EPMC5058770 | biostudies-literature
Project description:Background: Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of pro-inflammatory mediators, including TNFalpha and IL-6. Recent data suggest that during diet-induced obesity the phenotype of adipose-resident macrophages changes from alternatively activated macrophages towards a more classical and pro-inflammatory phenotype. Here, we explore the effect of PPARγ-activation on obesity-induced inflammation in 129SV mice fed a high fat diet for 20 weeks. High fat feeding increased bodyweight gain, adipose tissue mass and liver triglycerides. Rosiglitazone treatment further increased adipose mass, reduced liver triglycerides and changed adipose tissue morphology towards smaller adipocytes. Surprisingly, rosiglitazone markedly increased the number of macrophages in adipose tissue, as shown by immunohistochemical analysis and quantification of macrophage marker genes CD68 and F4/80+. In adipose tissue, markers for classically activated macrophages including IL-18 were down regulated whereas markers characteristic for alternatively activated macrophages (Arginase 1, IL-10) were up regulated by rosiglitazone. Importantly, conditioned media from rosiglitazone-treated alternatively activated macrophages neutralized the inhibitory effect of macrophages on 3T3-L1 adipocyte differentiation, suggesting that alternatively activated macrophages may be involved in mediating the effects of rosiglitazone on adipose tissue morphology and mass. Our results suggest that short term rosiglitazone treatment increases infiltration of alternatively activated macrophages in adipose tissue. The alternatively activated macrophages might play a role in PPARγ-dependent expansion and remodeling of adipose tissue. Keywords: metabolic state analysis Pure bred wild-type (129S1/SvImJ) male mice received a low fat diet or high fat diet for 21 weeks, providing 10 or 45% energy percent in the form of triglycerides (D12450B or D12451, Research Diets, New Brunswick, USA). The lard component in these diets was replaced by palm oil. In the last week of diet intervention, half of the mice receiving the HFD were switched to HFD supplemented with Rosiglitazone (0.01 % wt/wt). Animals were sacrificed in the fed state. Epididymal adipose tissue was excised and frozen in liquid nitrogen. Pooled RNA samples from 5 mice per experimental group were used for microarray analysis. Samples were hybridized on Affymetrix GeneChip Mouse Genome 430-2.0 plus arrays. Five microgram total RNA was labelled according to the Affymetrix One-cycle Target Labeling Assay, fragmented and hybridized according to Affymetrix's protocols.
2008-04-29 | E-GEOD-11295 | biostudies-arrayexpress
Project description:BackgroundMyeloid sarcoma (MS), including isolated and leukaemic MS, is an extramedullary myeloid tumour. MS can involve any anatomical site, but MS of the female genital tract is rare, with the ovaries and uterine body and cervix being the most commonly seen sites. Involvement of the vagina and vulva is extremely rare.Case summaryWe report a rare case of MS with involvement of the vulva and vagina and massive infiltration of the pelvic floor. A 26-year-old woman presented with a vulvar mass, irregular vaginal bleeding and night sweats. Magnetic resonance imaging demonstrated an ill-defined, irregular vulvovaginal mass with massive involvement of the paravaginal tissue, urethra, posterior wall of the bladder, and pelvic floor. The signal and enhancement of the huge mass was homogeneous without haemorrhage or necrosis. Positron emission tomography/computed tomography showed high fluorodeoxyglucose uptake by the mass. Peripheral blood count detected blast cells. Vulvovaginal mass and bone marrow biopsies were performed, and immunohistochemistry confirmed the diagnosis of acute myeloid leukaemia (M-2 type, FAB classification) and vulvovaginal MS. The patient was treated with induction chemotherapy followed by allogeneic haematopoietic stem cell transplantation, and achieved complete remission. A systemic review of the literature on vulvovaginal MS was conducted to explore this rare entity's clinical and radiological features.ConclusionVulvovaginal MS is extremely rare. Diagnosis of vulvovaginal MS can only be confirmed histopathologically. Even though its clinical and imaging presentations are nonspecific, MS should be considered in the differential diagnosis of a newly developed T2-hyperintense, homogeneously enhanced vulvovaginal mass, especially in a patient with suspected haematological malignancy.
| S-EPMC9403691 | biostudies-literature
Project description:Unlike several other tumor types, prostate cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate cancer progression and resistance to ICB, we analyzed prostate cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog Cxcl15 in prostate epithelial cells. We showed that these chemokines drove subsequent intratumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration, and highlight blockade of the IL-8/CXCR2 axis as a potential therapeutic intervention.
| S-EPMC9169571 | biostudies-literature
Project description:A subset of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients present pathological redistribution and aggregation of the nuclear protein fused in sarcoma (FUS) in the cytoplasm. Although FUS associates with the spliceosomal complex, no endogenous neuronal splicing targets have been identified. Here we identify Tau mRNA as a physiological splicing target of FUS. In mouse brain, FUS directly binds to Tau pre-mRNA, and knockdown of FUS in hippocampal neurons leads to preferential inclusion of Tau exons 3 and 10. FUS knockdown causes significant growth cone enlargement and disorganization reminiscent of Tau loss of function. These findings suggest that disturbed cytoskeletal function and enhanced expression of the neurodegeneration-associated Tau exon 10 might contribute to FTLD/ALS with FUS inclusions.
| S-EPMC3410390 | biostudies-literature
Project description:The BCL6 Corepressor (BCOR) is a component of a variant Polycomb repressive complex 1 (PRC1) that is essential for normal development. Recurrent mutations in the BCOR gene have been identified in acute myeloid leukaemia and myelodysplastic syndrome among other cancers; however, its function remains poorly understood. Here we examine the role of BCOR in haematopoiesis in vivo using a conditional mouse model that mimics the mutations observed in haematological malignancies. Inactivation of Bcor in haematopoietic stem cells (HSCs) results in expansion of myeloid progenitors and co-operates with oncogenic KrasG12D in the initiation of an aggressive and fully transplantable acute leukaemia. Gene expression analysis and chromatin immunoprecipitation sequencing reveals differential regulation of a subset of PRC1-target genes including HSC-associated transcription factors such as Hoxa7/9. This study provides mechanistic understanding of how BCOR regulates cell fate decisions and how loss of function contributes to the development of leukaemia.
| S-EPMC6430802 | biostudies-literature