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Prediction of isolated central nervous system relapses in pediatric acute lymphoblastic leukemia

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60926 | GEO | 2015/12/31

SECONDARY ACCESSION(S): PRJNA259828

REPOSITORIES: GEO

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Prediction of isolated central nervous system relapses in pediatric acute lymphoblastic leukemia

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

Value of lipocalin 2 as a potential biomarker for bacterial meningitis

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

Diagnosis-relapse in ALL

Project description:Almost a quarter of pediatric patients with Acute Lymphoblastic Leukemia (ALL) suffer from relapses. The biological mechanisms underlying therapy response and development of relapses have remained unclear. In an attempt to better understand this phenomenon, we have analyzed 41 matched diagnosis relapse pairs of ALL patients using genomeâ??wide expression arrays (82 arrays) on purified leukemic cells. In roughly half of the patients very few differences between diagnosis and relapse samples were found (â??stable groupâ??), suggesting that mostly extra-leukemic factors (e.g., drug distribution, drug metabolism, compliance) contributed to the relapse. Therefore, we focused our further analysis on 20 samples with clear differences in gene expression (â??skewed groupâ??), reasoning that these would allow us to better study the biological mechanisms underlying relapsed ALL. After finding the differences between diagnosis and relapse pairs in this group, we identified four major gene clusters corresponding to several pathways associated with changes in cell cycle, DNA replication, recombination and repair, as well as B cell developmental genes. We also identified cancer genes commonly associated with colon carcinomas and ubiquitination to be upregulated in relapsed ALL. Thus, about half of relapses are due to selection or emergence of a clone with deregulated expression of a genes involved in pathways that regulate B cell signaling, development, cell cycle, cellular division and replication. The study contains 41 pairs of samples taken from patients at diagnosis and relapse (a total of 82 arrays).

2010-03-23 | E-GEOD-18497 | biostudies-arrayexpress

IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL

Project description:Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis-relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A, and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS), were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk patients with IKZF1 deletions exhibited a ~12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone non-high-risk-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification. Affymetrix NspI 250k array data of 34 paired diagnosis and relapse samples of pediatric ALL. From 13 patients a complete remission sample was available. Four cases had 2 relapses.

2010-03-01 | GSE20353 | GEO

Diagnosis-relapse in ALL

Project description:Almost a quarter of pediatric patients with Acute Lymphoblastic Leukemia (ALL) suffer from relapses. The biological mechanisms underlying therapy response and development of relapses have remained unclear. In an attempt to better understand this phenomenon, we have analyzed 41 matched diagnosis relapse pairs of ALL patients using genome–wide expression arrays (82 arrays) on purified leukemic cells. In roughly half of the patients very few differences between diagnosis and relapse samples were found (“stable group”), suggesting that mostly extra-leukemic factors (e.g., drug distribution, drug metabolism, compliance) contributed to the relapse. Therefore, we focused our further analysis on 20 samples with clear differences in gene expression (“skewed group”), reasoning that these would allow us to better study the biological mechanisms underlying relapsed ALL. After finding the differences between diagnosis and relapse pairs in this group, we identified four major gene clusters corresponding to several pathways associated with changes in cell cycle, DNA replication, recombination and repair, as well as B cell developmental genes. We also identified cancer genes commonly associated with colon carcinomas and ubiquitination to be upregulated in relapsed ALL. Thus, about half of relapses are due to selection or emergence of a clone with deregulated expression of a genes involved in pathways that regulate B cell signaling, development, cell cycle, cellular division and replication.

2010-03-10 | GSE18497 | GEO

Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis

Project description:Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, we identified a specific border-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) – an autoimmune disease of the CNS – increased transcriptional diversity in blood, but increased cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. A new analytical approach, named cell set enrichment analysis (CSEA) identified a cluster-independent increase of follicular T helper (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promoted B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.

2019-12-10 | GSE138266 | GEO

Single cell mRNA profiles of CSF from children with BM

Project description:Purpose: Characterizing the cell heterogeneity of CSF during the BM development in children. Method: CSF samples were obtained via lumbar puncture from numbers of BM patients in different stages of disease progression. CSF cells were separated by direct centrifugation. A mimic assay based on QUARTZ-SEQ2 was adopted here for library preparations for scRNA-seq. Single CSF cells were sorted into two pre-prepared 384-well plates with cell lysis buffer by flow cytometry, in which each well contained a unique cell barcoding primer. An independent scRNA-seq library was constructed for 768 cells of each CSF sample, and was sequenced using a HiSeq X Ten sequencing system (Illumina). The generation of a cell-count matrix were processed in the combined workflow of UMI-tools and STAR. Secondary analysis were handled by Seurat package. Results: The heterogeneities of CSF cells in BM progression were deciphered. Multiple immune cell clusters in CSF were identified, including two neutrophils, two monocytes, one macrophage, four myeloid dendritic cells, five T cells, one natural killer cell, one B cell, one plasmacytoid dendritic cell, and one plasma cell subtype. Their population profiles and dynamics in the initial onset, remission, and recovery stages during BM progression were also characterized. Conclusions: This study conducted an in-depth exploration of the heterogeneities of CSF cells in BM progression, which provided novel insights into immune cell engagement in acute CNS infection.

2020-12-15 | GSE163194 | GEO

Transcriptional Mediator Subunit MED1/TRAP220 in Stromal Cells Is Involved in Hematopoietic Stem/Progenitor Cell Support through Osteopontin Expression

Project description:MED1/TRAP220, a subunit of the transcriptional Mediator/TRAP complex, is crucial for various biological events through its interaction with distinct activators such as nuclear receptors and GATA family activators. In hematopoiesis, MED1 plays a pivotal role in optimal nuclear receptor-mediated myelomonopoiesis and GATA-1-induced erythropoiesis. In this study, we present evidence that MED1 in stromal cells is involved in supporting hematopoietic stem and/or progenitor cells (HSPCs) through osteopontin (OPN) expression. We found that the proliferation of bone marrow (BM) cells cocultured with MED1 knockout (Med1-/-) mouse embryonic fibroblasts (MEFs) was significantly suppressed when compared to the control. Furthermore, the number of long-term culture-initiating cells (LTC-ICs) was attenuated for BM cells cocultured with Med1-/- MEFs. The vitamin D receptor (VDR)- and Runx2-mediated expression of OPN, as well as Mediator recruitment to the Opn promoter, was specifically attenuated in the Med1-/- MEFs. Addition of OPN to these MEFs restored the growth of cocultured BM cells and the number of LTC-ICs, both of which were attenuated by the addition of the anti-OPN antibody to Med1+/+ MEFs and to BM stromal cells. Consequently, MED1 in niche appears to play an important role in supporting HSPCs, by upregulating VDR- and Runx2-mediated transcription on the Opn promoter.

2010-08-31 | GSE22471 | GEO

Cytokine Polarized Bone Marrow Neutrophils Drive Axon Regeneration

Project description:The adult central nervous system (CNS) has a limited capacity for self-repair. Severed CNS axons typically do not regrow. There is an unmet need for treatments specifically designed to enhance neuronal viability, facilitate CNS axon regeneration, and ultimately restore lost neurological functions to individuals with traumatic CNS injury, multiple sclerosis, and stroke, among other disorders. Here we demonstrate that both mouse and human bone marrow (BM) neutrophils upregulate markers of alternative activation, and acquire the ability to promote neurite outgrowth, following polarization with a combination of recombinant interleukin-4 (IL-4) and granulocyte-colony stimulating factor (G-CSF). Moreover, adoptively transferring IL-4/G-CSF polarized BM neutrophils into experimental models of CNS injury resulted in significant axon regeneration within the optic nerve and spinal cord. The findings reported in this paper hold significant implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.

2023-12-01 | GSE244934 | GEO

Epigenomic Evolution of Diffuse Large B-cell Relapse

Project description:Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. Using ERRBS, we profiled genome-wide DNA methylation patterns of non-relapse DLBCL tumor samples at diagnosis, relaspe DLBCL patient samples at diagnosis and relaspe.

2015-04-14 | E-GEOD-66329 | biostudies-arrayexpress

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