Dataset Information

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34⁺ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia.

ABSTRACT: Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34⁺ hematopoietic cells was determined by multispectral imaging (MSI) in 147 BM biopsies (BMB) from patients with MDS, secondary acute myeloid leukemia (sAML), and controls. Results: In MDS and sAML samples, a high inter-tumoral immune cell heterogeneity in spatial proximity to CD34⁺ blasts was found that was independent of genetic alterations, but correlated to blast counts. In controls, no CD8⁺ and FOXP3⁺ T cells and only single MUM1p⁺ B/plasma cells were detected in an area of ?10 ?m to CD34⁺ HSPC. Conclusions: CD8⁺ and FOXP3⁺ T cells are regularly seen in the 10 ?m area around CD34⁺ blasts in MDS/sAML regardless of the course of the disease but lack in the surrounding of CD34⁺ HSPC in control samples. In addition, the frequencies of immune cell subsets in MDS and sAML BMB differ when compared to control BMB providing novel insights in immune deregulation.

SUBMITTER: Bauer M

PROVIDER: S-EPMC7825771 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia.

Bauer Marcus M Vaxevanis Christoforos C Al-Ali Haifa Kathrin HK Jaekel Nadja N Naumann Christin Le Hoa CLH Schaffrath Judith J Rau Achim A Seliger Barbara B Wickenhauser Claudia C

Cancers 20210107 2

Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34+ hematopoietic cells was determined by multispectral imaging ( ...[more]

PMID: 33430322

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Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

Project description:ObjectiveThis study aims to investigate and analyze the differentially expressed genes (DEGs) in CD34 + hematopoietic stem cells (HSCs) from patients with myelodysplastic syndromes (MDS) through bioinformatics analysis, with the ultimate goal of uncovering the potential molecular mechanisms underlying pathogenesis of MDS. The findings of this study are expected to provide novel insights into clinical treatment strategies for MDS.MethodsInitially, we downloaded three datasets, GSE81173, GSE4619, and GSE58831, from the public Gene Expression Omnibus (GEO) database as our training sets, and selected the GSE19429 dataset as the validation set. To ensure data consistency and comparability, we standardized the training sets and removed batch effects using the ComBat algorithm, thereby integrating them into a unified gene expression dataset. Subsequently, we conducted differential expression analysis to identify genes with significant changes in expression levels across different disease states. In order to enhance prediction accuracy, we incorporated six common predictive models and trained them based on the filtered differential gene expression dataset. After comprehensive evaluation, we ultimately selected three algorithms-Lasso regression, random forest, and support vector machine (SVM)-as our core predictive models. To more precisely pinpoint genes closely related to disease characteristics, we utilized the aforementioned three machine learning methods for prediction and took the intersection of these prediction results, yielding a more robust list of genes associated with disease features. Following this, we conducted in-depth analysis of these key genes in the training set and validated the results independently using the GSE19429 dataset. Furthermore, we performed differential analysis of gene groups, co-expression analysis, and enrichment analysis to delve deeper into the mechanisms underlying the roles of these genes in disease initiation and progression. Through these analyses, we aim to provide new insights and foundations for disease diagnosis and treatment. Figure illustrates the data preprocessing and analysis workflow of this study.ResultsOur analysis of differentially expressed genes (DEGs) in CD34+ hematopoietic stem cells (HSCs) from patients with myelodysplastic syndromes (MDS) revealed significant differences in gene expression patterns compared to the control group (individuals without MDS). Specifically, the expression levels of two key genes, IRF4 and ELANE, were notably downregulated in CD34+ HSCs of MDS patients, indicating their downregulatory roles in the pathological process of MDS.ConclusionThis study sheds light on the potential molecular mechanisms underlying MDS, with a particular focus on the pivotal roles of IRF4 and ELANE as key pathogenic genes. Our findings provide a novel perspective for understanding the complexity of MDS and exploring therapeutic strategies. They may also guide the development of precise and effective treatments, such as targeted interventions directed against these genes.

Dataset Information

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34⁺ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia.

Publications

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34<sup>+</sup> Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia.

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