Targeted deep sequencing of CD34+ cells from peripheral blood can reproduce bone marrow molecular profile in myelodysplastic syndromes.
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ABSTRACT:
SUBMITTER: Martin R
PROVIDER: S-EPMC6001632 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
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Targeted deep sequencing of CD34+ cells from peripheral blood can reproduce bone marrow molecular profile in myelodysplastic syndromes.
Martin Roman R Acha Pamela P Ganster Christina C Palomo Laura L Dierks Sascha S Fuster-Tormo Francisco F Mallo Mar M Ademà Vera V Gómez-Marzo Paula P De Haro Nuri N Solanes Neus N Zamora Lurdes L Xicoy Blanca B Shirneshan Katayoon K Flach Johanna J Braulke Friederike F Schanz Julie J Kominowski Arkadiusz A Stromburg Martin M Brockmann Alina A Trümper Lorenz L Solé Francesc F Haase Detlef D
American journal of hematology 20180410 6
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Project description:Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies. Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities, myelodysplasia (a pathological definition of abnormal bone marrow structure), ineffective hematopoiesis resulting in blood cytopenia, and a propensity to evolve into acute myelogenous leukemia. Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS, there is an increased appreciation of the contribution of specific microenvironments, niches, in the pathogenesis of MDS and response to treatment. In physiologic hematopoiesis, niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells. In MDS and other hematological malignancies, altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy. In this review, we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies, with an emphasis on MDS.
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Project description:Myelodysplastic syndromes (MDS) are a group of hematologic neoplasms accompanied by dysplasia of the bone marrow hematopoietic cells with cytopenia. Detecting dysplasia is important in the diagnosis of MDS, but it takes considerable time and effort. Also, since the assessment of dysplasia is subjective and difficult to quantify, a more efficient tool is needed for quality control and standardization of bone marrow aspiration smear interpretation. In this study, we developed and evaluated an algorithm to automatically discriminate hematopoietic cell lineages and detect dysplastic cells in bone marrow aspiration smears using deep learning technology. Bone marrow aspiration images were acquired from 34 patients diagnosed with MDS and from 24 normal bone marrow slides. In total, 8065 cells were classified into eight categories: normal erythrocytes, normal granulocytes, normal megakaryocytes, dysplastic erythrocytes, dysplastic granulocytes, dysplastic megakaryocytes, blasts, and others. The algorithm demonstrated acceptable performance in classifying dysplastic cells, with an AUC of 0.945-0.996 and accuracy of 0.912-0.993. The algorithm developed in this study could be used as an auxiliary tool for diagnosing patients with MDS and is expected to contribute to shortening the time required for MDS bone marrow aspiration diagnosis and standardizing visual reading.
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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed "antioxidogram," for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM blasts [GLRX family]); (2) increased expression of enzymes detoxifying H2O2 (MDS with 5% to 19% BM blasts [PRDX and GPX families]); and finally (3) decreased expression of these enzymes in sAML. The antioxidant score (AO-Score) defined by logistic regression from the expression levels of transcripts made it possible to stage disease progression and, interestingly, this AO-Score was independent of the revised International Scoring System. Altogether, this study demonstrates that MDS and sAML present an important disturbance of redox metabolism, especially in BM stem and progenitor cells and that the specific molecular antioxidant response parameters (antioxidogram, AO-Score) could be considered as useful biomarkers for disease diagnosis and follow-up.
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Project description:The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB,and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis.
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs functioning as regulators of hematopoiesis. Their differential expression patterns have been linked with various pathological processes originating from hematopoietic stem cells (HSCs). However, limited information is available regarding the role of miRNAs in myelodysplastic syndrome (MDS). Using miRNA arrays, we measured expression of 1,145 miRNAs in CD34+ bone marrow cells obtained from 39 MDS and acute myeloid leukemia (AML) evolved from MDS patients, and compared them with those of six healthy donors. Differential miRNA expression was analyzed and a panel of upregulated (n=13) and downregulated (n=9) miRNAs were found (P<0.001) in MDS/AML patients. An increased expression of a large miRNA cluster mapped within the 14q32 locus was detected. Differences in miRNA expression of MDS subtypes showed a distinction between early and advanced MDS; an apparent dissimilarity was observed between RAEB-1 and RAEB-2 subtypes. In early MDS, we monitored upregulation of proapoptotic miR-34a, which may contribute to the increased apoptosis of HSCs. Patients with 5q deletion were characterized by decreased levels of miR-143(*) and miR-378 mapped within the commonly deleted region at 5q32. This is an early report describing differential expression in MDS CD34+ cells, likely reflecting their disease-specific regulation.
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Project description:BackgroundMyelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective haematopoiesis and immune deregulation. Emerging evidence has shown the effect of bone marrow (BM) endothelial progenitor cells (EPCs) in regulating haematopoiesis and immune balance. However, the number and functions of BM EPCs in patients with different stages of MDS remain largely unknown.MethodsPatients with MDS (N = 30), de novo acute myeloid leukaemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. MDS patients were divided into lower-risk MDS (N = 15) and higher-risk MDS (N = 15) groups according to the dichotomization of the Revised International Prognostic Scoring System. Flow cytometry was performed to analyse the number of BM EPCs. Tube formation and migration assays were performed to evaluate the functions of BM EPCs. In order to assess the gene expression profiles of BM EPCs, RNA sequencing (RNA-seq) were performed. BM EPC supporting abilities of haematopoietic stem cells (HSCs), leukaemia cells and T cells were assessed by in vitro coculture experiments.ResultsIncreased but dysfunctional BM EPCs were found in MDS patients compared with HDs, especially in patients with higher-risk MDS. RNA-seq indicated the progressive change and differences of haematopoiesis- and immune-related pathways and genes in MDS BM EPCs. In vitro coculture experiments verified that BM EPCs from HDs, lower-risk MDS, and higher-risk MDS to AML exhibited a progressively decreased ability to support HSCs, manifested as elevated apoptosis rates and intracellular reactive oxygen species (ROS) levels and decreased colony-forming unit plating efficiencies of HSCs. Moreover, BM EPCs from higher-risk MDS patients demonstrated an increased ability to support leukaemia cells, characterized by increased proliferation, leukaemia colony-forming unit plating efficiencies, decreased apoptosis rates and apoptosis-related genes. Furthermore, BM EPCs induced T cell differentiation towards more immune-tolerant cells in higher-risk MDS patients in vitro. In addition, the levels of intracellular ROS and the apoptosis ratios were increased in BM EPCs from MDS patients, especially in higher-risk MDS patients, which may be therapeutic candidates for MDS patients.ConclusionOur results suggest that dysfunctional BM EPCs are involved in MDS patients, which indicates that improving haematopoiesis supporting ability and immuneregulation ability of BM EPCs may represent a promising therapeutic approach for MDS patients.
| S-EPMC8962499 | biostudies-literature
Project description:IntroductionThe bone marrow (BM) microenvironment plays an important role in the pathogenesis of myelodysplastic syndromes (MDS) through a reciprocal interaction with resident BM hematopoietic cells. We investigated the differences between BM mesenchymal stromal cells (MSCs) in MDS and normal individuals and identified genes involved in such differences.Materials and methodsBM-derived MSCs from 7 MDS patients (3 RCMD, 3 RAEB-1, and 1 RAEB-2) and 7 controls were cultured. Global gene expression was analyzed using a microarray.ResultWe found 314 differentially expressed genes (DEGs) in RCMD vs. control, 68 in RAEB vs. control, and 51 in RAEB vs. RCMD. All comparisons were clearly separated from one another by hierarchical clustering. The overall similarity between differential expression signatures from the RCMD vs. control comparison and the RAEB vs. control comparison was highly significant (p = 0), which indicates a common transcriptomic response in these two MDS subtypes. RCMD and RAEB simultaneously showed an up-regulation of interferon alpha/beta signaling and the ISG15 antiviral mechanism, and a significant fraction of the RAEB vs. control DEGs were also putative targets of transcription factors IRF and ICSBP. Pathways that involved RNA polymerases I and III and mitochondrial transcription were down-regulated in RAEB compared to RCMD.ConclusionGene expression in the MDS BM microenvironment was different from that in normal BM and exhibited altered expression according to disease progression. The present study provides genetic evidence that inflammation and immune dysregulation responses that involve the interferon signaling pathway in the BM microenvironment are associated with MDS pathogenesis, which suggests BM MSCs as a possible therapeutic target in MDS.
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Project description:We aimed to determine the impact of the common mutations on the transcriptome in myelodysplastic syndromes (MDS). We linked genomic data with gene expression microarray data and we deconvoluted the expression of genes into contributions stemming from each genetic and cytogenetic alteration, providing insights into how driver mutations interfere with the transcriptomic state. We modelled the influence of mutations and expression changes on diagnostic clinical variables as well as survival.
2015-01-06 | GSE58831 | GEO
Project description:Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammation-related changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC.
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Project description:The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS). However, the clinical importance of BM fibrosis is not clear in therapy-related MDS. We retrieved all therapy-related MDS (t-MDS) cases (n = 266) diagnosed at our hospital over a 10-year period (2003-2012). Reticulin and trichrome stains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin and eosin-stained slide. BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis. Moderate/severe BM fibrosis was found in 47 (17%) patients. Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p = 0.039) and higher numbers of circulating blasts (p = 0.051) but with similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms. Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p < 0.001) in the fibrotic group. Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, -5 and -17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p = 0.031 and p = 0.043, respectively). With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation and a comparable overall survival in univariate and multivariate analyses. Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features. However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy-related MDS.
| S-EPMC4190057 | biostudies-literature