7fe20ee9-1eca-4d10-afaf-fe36dfdab511 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001008183 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:KMT2A-rearranged (KMT2A-r) infant leukaemia can present as a lymphoid, myeloid or mixed lineage leukaemia and frequently involves the central nervous system (CNS), yet the impact of this lineage diversity and plasticity on CNS involvement remains poorly understood. Using a fully murine model of KMT2A-AFF1+ mixed lineage infant leukaemia, we investigated how the CNS niche influences the phenotype and function of leukaemia propagating cells (LPC). Previously defined bone marrow (BM)-derived LPCs were transplanted and shown to engraft the CNS, although not equally; LK/CLP cells were consistently underrepresented in the niche. Transplants of CNS-derived LPCs, modelling relapse, demonstrated reduced systemic repopulation capacity, with many recipients exhibiting stable long-term engraftment without developing overt leukaemia, a phenomenon not observed in BM-derived transplants. Transcriptomic profiling of matched CNS- and BM-derived LPCs revealed enrichment of pathways involved in hypoxia, lipid and cholesterol homeostasis, and inflammatory signalling. Notably, LPC subsets that successfully adapted to the CNS niche upregulated lipid and fatty acid metabolic programmes. CNS-derived LPCs showed increased expression of genes involved in T cell immune modulation, suggesting a skew to a more immunosuppressive environment. These findings indicate that the CNS niche imposes lasting metabolic, functional, and immunological constraints on leukemic cells, impairing their ability to reestablish systemic disease. We show that the CNS niche imposes selective pressures and causes functional reprogramming of mixed lineage LPCs, affecting their systemic repopulation capacity and, we hypothesise, immune cell interactions. We further believe this study has relevance to primary mixed lineage infant leukaemia and, increasingly important, lineage-switched infant leukaemia.
2026-03-05 | GSE303671 | GEO
Project description:Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has a poor prognosis and remains a therapeutic challenge with few recent advances in therapy. Leptomeningeal disease is particularly common in the high risk subgroup of KMT2A-rearranged B-ALL (KMT2A-r B-ALL). Here we performed transcriptional and proteomic profiling of leukemia cells from bone marrow (BM) and CNS-disseminated disease in KMT2A-r B-ALL xenografts. CNS disease exhibited stemness traits and metabolic reprogramming previously associated with chemotherapy resistance. Genes governing mRNA translation were upregulated in CNS samples, a finding confirmed in cohorts of KMT2A-r B-ALL patients with CNS involvement. This upregulation was functionally important for CNS disease as the mRNA translational inhibitor omacetaxine mepesuccinate (OMA) significantly reduced leptomeningeal disease burden in xenografts. Proteomic analysis demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3), a known driver of leptomeningeal metastasis in solid tumours, pointing to a convergent mechanism for this route of metastasis in multiple cancers. Pharmacological inhibition of C3a signaling suppressed CNS dissemination, whereas C3a receptor activation increased CNS disease. Overall, our study identifies mRNA translation and a set of secreted proteins as key mediators of CNS dissemination in KMT2A-r B-ALL. Therapeutic targeting of these dependencies represents a novel approach to prevent or treat leptomeningeal disease.
2023-03-11 | PXD022411 | Pride
Project description:Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing, transcriptional and proteomic profiling of paired leukemia infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3) and drug targeting of C3 influenced CNS disease in xenografts. CNS infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies therapeutic targeting of mRNA translation as a novel therapeutic approach for B-ALL leptomeningeal disease.
| EGAS00001005647 | EGA
Project description:Infant B-cell acute lymphoblastic leukaemia (B-ALL) is a rare, aggressive entity characterised by KMT2A-rearrangements and poor outcomes. One of the unique features of KMT2A-rearranged infant ALL contributes to these poor outcomes is a particularly high rate of central nervous system (CNS) involvement. In this study we used an immune competent KMT2A-AFF1+ infant B-ALL murine model (https://doi.org/10.1182/blood.2020006610) to explore the cell-intrinsic and cell-extrinsic mechanisms that underpin this clinically significant complication. We show novel functional impacts on leukaemia propagating cells (LPCs) following exposure to the CNS niche which results in unique leukaemia repopulation dynamics. Transcriptomic and immune cell profiling comparisons by niche showed differences in the immune microenvironment between the CNS and bone marrow (BM) niches. We observe the CNS niche demonstrates supressed T cell and macrophage activity which may be part of a wider CNS niche-specific immune escape mechanism. Our transcriptomic comparisons by niche also led us to explore the role of PI3K pathway activation in the propagation of leukaemia cells within the CNS niche. We identify miR-93 as a possible master regulator of this process. The importance of miR-93 is emphasised as it is shown to be upregulated in CNS leukaemia cells across multiple murine KMT2A-AFF1 B-ALL model systems and in primary KMT2A-AFF1 B-ALL patient samples. We conclude by showing impaired CNS engraftment of leukaemia cells upon miR-93 knockdown, cementing its importance in CNS leukaemia biology.
2026-04-12 | GSE280505 | GEO
Project description:Purpose: To investigate metabolic adaptation of leukaemia in two different microenvironments: central nervous system and spleen Methods: The REH (TEL-AML1) cell line representing a standard-risk subtype was used. Cells were transplanted into immunodeficient mice. CNS tropism was demonstrated and ALL blasts invaded the leptomeninges in a timeframe ranging from 4 to 5 weeks. At experimental endpoint, blasts were retrieved from the CNS and periphery (spleen), and their gene expression profiles were compared using RNA-sequencing. The raw reads were pre-processed with Cutadapt v.1.5 and Sickle v.0.940 software. Transcript expression quantification was performed using Kallisto v.0.42.4 software against combined human and mouse transcriptomes, Ensembl GRCh38.79 and GRCm38.78, respectively. Read counts related to human transcripts were collected, rounded, and summarized into gene specific read counts. Gene-based differential expression analysis was done with DESeq2 R-package. Preprocessed RNA expression data from RNA sequencing was analysed further using single sample gene set enrichment analysis (ssGSEA). Results: The human REH cells’ gene expression profiles clustered according to site of colonization in the transplanted mice; CNS versus spleen. Top differentially expressed genes were associated with cellular metabolism or stress responses. ssGSEA analysis identified positive correlation of lipid and lipoprotein metabolism signatures in CNS-derived cells, with particular propensity towards fatty acid synthesis. On the other hand, oxidative phosphorylation processes, linked to fatty acid degradation, were negatively correlated with CNS involvement and enriched in REH cells from the spleen of transplanted mice. Conclusions: We demonstrate that leukaemic cells undergo widespread dynamic rewiring of metabolism when switching from bone marrow to CNS microenvironments, resulting in altered therapeutic vulnerabilities. We observed a strong fatty-acid synthesis signature in CNS leukaemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player.
2020-07-08 | GSE135114 | GEO
Project description:Purpose: To investigate metabolic adaptation of leukaemia in two different microenvironments: central nervous system and spleen Methods: The SEM (MLL-AF4) cell-line representing a high-risk subtype was used. Cells were transplanted into immunodeficient mice. CNS tropism was demonstrated and blasts invaded the leptomeninges in a timeframe ranging from 4 to 5 weeks. At experimental endpoint, blasts were retrieved from the CNS and periphery (spleen), and their gene expression profiles were compared using RNA-sequencing. The raw reads were pre-processed with Cutadapt v.1.5 and Sickle v.0.940 software. Transcript expression quantification was performed using Kallisto v.0.42.4 software against combined human and mouse transcriptomes, Ensembl GRCh38.79 and GRCm38.78, respectively. Read counts related to human transcripts were collected, rounded, and summarized into gene specific read counts. Gene-based differential expression analysis was done with DESeq2 R-package. Preprocessed RNA expression data from RNA sequencing was analysed further using single sample gene set enrichment analysis (ssGSEA). Results: The human SEM cells’ gene expression profiles clustered according to site of colonization in the transplanted mice; CNS versus spleen. The top differentially expressed genes were associated with cellular metabolism or stress responses. ssGSEA analysis identified positive correlation of lipid and lipoprotein metabolism signatures in CNS-derived cells, with particular propensity towards fatty acid synthesis. On the other hand, oxidative phosphorylation processes, linked to fatty acid degradation, were negatively correlated with CNS involvement and enriched in SEM cells from the spleen of transplanted mice. Conclusions: We demonstrate that leukaemic cells undergo widespread dynamic rewiring of metabolism when switching from bone marrow to CNS microenvironments, resulting in altered therapeutic vulnerabilities. We observed a strong fatty-acid synthesis signature in CNS leukaemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player.
2020-07-08 | GSE135113 | GEO
Project description:Background. Flow cytometry (FCM) identifies leukemic blasts in cerebrospinal fluid (CSF) in approximately 30% of children with acute lymphoblastic leukemia (ALL), whereas conventional cytospin preparations frequently miss such involvement. <br>Procedure. To explore biological properties of leukemic cells that migrate into central nervous system (CNS), we compared gene expression profiles of leukemic cells from 26 patients with CNS involvement and 138 patients without CNS leukemia as determined by FCM and/or cytospin preparations. Results were validated by real-time quantitative PCR (qPCR). <br>Results. We found the cysteine endopeptidase legumain (LGMN) that plays a role in hydrolysis of proteins and small molecules to be significantly differentially expressed between FCM+ and FCM- B-cell precursor (BCP) ALL patients. When LGMN expression was validated by qPCR it stayed differentially expressed between FCM+ and FCM- BCP-ALL patients (P=0.006), and also between FCM+ and cytospin-negative BCP-ALL patients (P=0.01). In multivariate regression analysis including sex, age and WBC, LGMN expression levels above population median were associated with an odds ratio of 9.1 for CNS involvement as determined by FCM compared with expression less than the median (95% CI, 1.26 to 65.50; P=0.03). Conclusions. The use of more sensitive methods for detecting and quantifying CNS involvement, such as FCM, may facilitate detection of markers of leukemia biology, such as LGMN, which could have therapeutical implications for future CNS-directed therapy.<br>FCM+: Patients had leukemic cells in the cerebrospinal fluid (CSF) detected by flow cytometry and no blood contamination. FCM-: Patients had no leukemic cells in the CSF detected by flow cytometry with or without blood contamination.<br>CNS1: No leukemic cells in CSF detected by cytospin examination with or without blood contamination and no other clinical signs of central nervous system (CNS) leukaemia. CNS2: CSF leukocyte count <5 x106/µL with blasts on cytospin examination and no blood contamination. CNS3: CSF leukocyte count >5 x106/µL with blasts on cytospin examination and no blood contamination, and/or cranial nerve palsy, and/or CNS leukaemia by neuroimaging.
2019-01-01 | E-MTAB-4985 | biostudies-arrayexpress
Project description:Maintaining cholesterol homeostasis is essential for health of all animal cells. Because of blood-brain barrier, de novo cholesetrol biosynthesis and intercellular cholesterol transport is thought to maintain cholesterol homeostasis within the central nervous system (CNS). Here, we showed that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), regulates SREBF2-mediated cholesterol metabolism in the central nervous system (CNS). Unbiased transcriptomic analysis of mice with oligodendroglial TDP-43 deletion revealed a progressive and pathway-wide disruption in the cholesterol metabolism correlating with reduced myelination and cholesterol level. Molecularly, TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins in the cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. Depletion of TDP-43 leads to reduced SREBF2 and cholesterol level in vitro and in vivo. The cholesterol reduction can be rescued by reintroducing either the nuclear portion of SREBF2 or LDLR, the latter of which is the receptor for cholesterol-containing low-density lipoproteins (LDLs). Furthermore, LDLR are observed to co-aggregate with pathological TDP-43 in oligodendrocytes of FTD patients and motor neurons of sporadic ALS patients. Taken together, our data indicates that TDP-43 is required to maintain SREBF2-dependent cholesterol homeostasis in the CNS, and disturbance of cholesterol metabolism may be involved in ALS, FTD and TDP-43 proteinopathies-related disease.
2021-07-01 | GSE133047 | GEO
Project description:Objectives: Central nervous system (CNS) infections are common causes of morbidity and mortality worldwide. We aimed to discover protein biomarkers that could rapidly and accurately identify the likely cause of the infections, essential for clinical management and improving outcome. Methods: We applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential diagnostic biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in Vietnam. Results: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis (BM) other than tuberculous meningitis. The analysis of the validation cohort showed that LCN2 could discriminate BM from other CNS infections (including tuberculous meningitis, cryptococcal meningitis and viral/antibody-mediated encephalitis), with the sensitivity: 0.88 (95% confident interval (CI): 0.77-0.94), the specificity: 0.91 (95%CI: 0.88-0.94) and the diagnostic odd ratio: 73.8 (95%CI: 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2, CSF leukocytes, glucose, protein and lactate resulted in the highest diagnostic performance for BM (area under receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99). Conclusions: Our results suggest that LCN2 is a sensitive and specific biomarker for discriminating BM from a broad spectrum of other CNS infections. A prospective study is needed to assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections..
2020-08-20 | PXD020510 | Pride
Project description:Here we show that muscarinic type-1 (Chrm1) signaling in the central nervous system (CNS) promotes G-CSF-elicited HSC migration from the BM. Blockade of Chrm1 in the CNS, but not the periphery, reduced HSC mobilization. In Chrm1−⁄− mice, reduced mobilization was rescued by wild-type parabionts, suggesting the contribution of a soluble factor. We found that corticosterone levels were dramatically reduced in the BM, and its exogenous administration normalized the mobilization deficit of Chrm1−⁄− animals. Chrm1−⁄− HSCs have reduced nuclear glucocorticoid receptors (Nr3c1) and alterations in the expression of actin-organizing molecules. Polymerized actin formation and HSC mobilization are also impaired in mice harboring Nr3c1-deficient hematopoietic cells.
2017-02-15 | GSE76350 | GEO