Discovery of Central Nervous System Infiltration in Zebrafish T Cell Acute Lymphoblastic Leukemia
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE62541 | GEO | 2017/09/29
SECONDARY ACCESSION(S): PRJNA264381
REPOSITORIES: GEO
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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:Background In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Minimal residual disease diagnostics predict most bone marrow (BM) relapses, but likely cannot predict isolated CNS relapses. Consequently, CNS relapses may become relatively more important. Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Methods Gene expression profiles of ALL cells from cerebrospinal fluid (CSF) and ALL cells from BM were compared and differences were confirmed by real-time quantitative PCR. For a selected set of overexpressed genes, protein expression levels of ALL cells in CSF at relapse and of ALL cells in diagnostic BM samples were evaluated by 8-color flow cytometry. Results CSF-derived ALL cells showed a clearly different gene expression profile than BM-derived ALL cells, with differentially-expressed genes (including SCD and OPN) involved in survival and apoptosis pathways and linked to the JAK-STAT pathway. Flowcytometric analysis showed that a subpopulation of ALL cells (>1%) with a â??CNS signatureâ?? (SCD positivity and increased OPN expression) was already present in BM at diagnosis in ALL patients who later developed a CNS relapse, but was <1% or absent in virtually all other patients. Conclusions The presence of a subpopulation of ALL cells with a â??CNS signatureâ?? at diagnosis may predict isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity. We compared gene expression profiles of ALL cells obtained from cerebrospinal fluid (n=8) with profiles of ALL cells obtained from bone marrow at diagnosis (n=22) or at relapse (n=20)
2015-12-31 | E-GEOD-60926 | biostudies-arrayexpress
Project description:Background In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Minimal residual disease diagnostics predict most bone marrow (BM) relapses, but likely cannot predict isolated CNS relapses. Consequently, CNS relapses may become relatively more important. Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Methods Gene expression profiles of ALL cells from cerebrospinal fluid (CSF) and ALL cells from BM were compared and differences were confirmed by real-time quantitative PCR. For a selected set of overexpressed genes, protein expression levels of ALL cells in CSF at relapse and of ALL cells in diagnostic BM samples were evaluated by 8-color flow cytometry. Results CSF-derived ALL cells showed a clearly different gene expression profile than BM-derived ALL cells, with differentially-expressed genes (including SCD and OPN) involved in survival and apoptosis pathways and linked to the JAK-STAT pathway. Flowcytometric analysis showed that a subpopulation of ALL cells (>1%) with a “CNS signature” (SCD positivity and increased OPN expression) was already present in BM at diagnosis in ALL patients who later developed a CNS relapse, but was <1% or absent in virtually all other patients. Conclusions The presence of a subpopulation of ALL cells with a “CNS signature” at diagnosis may predict isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity.
2015-12-31 | GSE60926 | GEO
Project description:Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central nervous system positivity in T-cell acute lymphoblastic leukemia (odds ratio=11.00, 95% confidence interval, 2.00-60.62). We propose zeta-chain-associated protein kinase 70, CCR7 and CXCR4 as markers of central nervous system infiltration in acute lymphoblastic leukemia warranting prospective investigation.
| S-EPMC5286942 | biostudies-literature
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:Primary familial brain calcification (PFBC) is a rare neurodegenerative and neuropsychiatric disorder characterized by bilateral and symmetric brain calcification along the microvessels or inside neuronal cells in the basal ganglia, thalamus, and cerebellum. Neurological symptoms typically include movement disorders, cognitive impairment, and neuropsychiatric signs. Slc20a2 homozygous (HO) knockout mice can simulate the phenotype of brain calcification observed in humans. However, the cellular and molecular mechanisms associated with brain calcification, particularly at an extremely early stage (before calcification emerges), remain largely unknown. Herein, we quantified central nervous system (CNS)-infiltrating immune cells in different age groups and found that CD45+CD3+ T cells were significantly increased in the brain parenchyma even in the pre-calcification stage of 1-month-old Slc20a2-HO mice. Further immunophenotyping demonstrated that CD3+CD4-CD8- and CD3+CD4+ T cells were the two main subtypes increased in the brain. The accumulation of total T cells appears to be associated with the severity of brain calcification. Paracellular and transcellular permeability of the blood-brain barrier increased in endothelial cells of brain microvessels in Slc20a2-HO mice. The expression of endothelial cell adhesion molecules was increased, while that of tight and adherens junction proteins was decreased, reflecting the molecular basis of T cell recruitment to endothelial cells and paracellular migration into the brain. IgG and albumin assays revealed an increased leakage of endothelial cells and the process of T cell transcellular migration was captured by immunoelectron microscopy, suggesting the enhancement of transcytosis or endocytosis in brain endothelial cells of Slc20a2-HO mice. The sphingosine 1-phosphate receptor modulator, FTY720, could significantly inhibit brain calcification, probably by reducing the CNS infiltration of T cells, subsequently modulating neuroinflammation, and enhancing the phagocytosis of CNS resident immune cells. This study demonstrated that CNS-infiltrating T cells were associated with the progression of brain calcification and suggested that the impairment of blood-brain barrier permeability, which was closely related to T cell invasion into the CNS, could be explained by an increase in the paracellular and transcellular pathways of brain endothelial cells in Slc20a2-HO mice. Moreover, FTY720 was a potential drug that could be used to treat patients with PFBC in the future
2022-11-23 | GSE218335 | 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:Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Keywords: disease state analysis
2008-05-10 | GSE11392 | GEO
Project description:Traumatic injuries to the central nervous system (CNS) affect millions of people worldwide yet lack an effective treatment. These injuries contain infiltrating immune cells that can promote tissue repair and could be exploited for therapeutic benefit. Here, using single-cell RNA-sequencing of T cells infiltrating the injured CNS we demonstrate their clonal expansion and antigen specificity towards CNS derived self-peptides. We confirm the beneficial effect of these injury-associated autoimmune CD4+ T cells in murine models of optic nerve and spinal cord injury. Subsequently, using mRNA-based transient T cell receptor (TCR) reconstitution, we demonstrate a therapeutic T cell strategy to alleviate CNS injury. Treatment of CNS-injured mice with this therapy improved locomotion and alleviated histological signs of damage, through regulation of myeloid cells, without detrimental autoimmune side effects. This strategy provides a means of developing custom-designed T cell therapies for CNS injury, and possibly for other neurodegenerative disorders.
2024-07-23 | GSE216388 | GEO