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Project description:The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Krüppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.
| S-EPMC7340798 | biostudies-literature
Project description:A Distinct Epigenetic Program Underlies the 1 7 Translocation in Myelodysplastic Syndromes (MDS)
| PRJNA486339 | ENA
Project description:The unbalanced translocation t(1;7)(q10;p10), generating 1q trisomy and 7q monosomy, is due to centromere-centromere juxtaposition. This dicentric chromosome is a recurrent change in myelodysplastic syndromes (MDS), with half the cases arising after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We first identified a comprehensive genetic and epigenetic landscape of MDS with dic(1;7)(q10;p10) and compared it to normal controls and other therapy-related Myeloid Neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and of genes related to lipid metabolism, and upregulation of p53 signaling were the most relevant biological features of dicentric-positive MDS. Despite 1q trisomy, more than 50% of 1q deregulated genes were downregulated. This partial gene dosage effect was clarified by epigenetic analysis, which highlighted the presence of a specific hypermethylated pattern on 1q. Furthermore, in a supervised analysis, hypermethylation in all dicentrics clustered at intronic enhancers and was enriched for Krüppel-like transcription factors binding sites. Low expression levels of enhancer putative target genes accounted for more than 30% of the downregulated signature. Our findings demonstrate that alteration of centromeric DNA in dic(1;7) cases imposes a specific transcriptional program, driven by a unique epigenomic signature.
2019-09-01 | GSE118477 | GEO
Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased BM cellularity (NH-MDS), some have hypocellular BM (h-MDS). The reports concerning the differences in genetic alterations between h-MDS and NH-MDS patients are limited. In this study, 369 MDS patients diagnosed according to the WHO 2008 criteria were recruited. h-MDS patients had lower PB white blood cell and blast counts, and lower BM blast percentages, than those with NH-MDS. h-MDS was closely associated with lower-risk MDS, defined by the International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R). IPSS-R could properly predict the prognosis in h-MDS (P<0.001) as in NH-MDS patients. The h-MDS patients had lower incidences of RUNX1, ASXL1, DNMT3A, EZH2 and TP53 mutations than NH-MDS patients. The cumulated incidence of acute leukemic transformation at 5 years was 19.3% for h-MDS and 40.4% for NH-MDS patients (P= 0.001). Further, the patients with h-MDS had longer overall survival (OS) than those with NH-MDS (P= 0.001), and BM hypocellularity remains an independent favorable prognostic factor for OS irrespective of age, IPSS-R, and gene mutations. Our findings provide evidence that h-MDS indeed represent a distinct clinico-biological subgroup of MDS and can predict better leukemia-free survival and OS.
| S-EPMC5325355 | biostudies-literature
Project description:Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance or direct an antileukemic effect, and therapies which target immunological markers on MDS progenitors themselves. Examples of the former include immune checkpoint inhibitors, immunomodulatory therapies, and vaccines, among others, while examples of the latter include antibody-drug conjugate therapies and naked antibodies; while bispecific antibodies and modified T-cells (such as CAR-T therapies) bridge both therapeutic modalities. In this review, we will discuss the rationale for the above therapies, clinical results to date, and potential future directions for investigation.
| S-EPMC8860886 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between ´normal´, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice.
| S-EPMC5650276 | biostudies-literature
Project description:A 10K cDNA microarray was used to compare neutrophil RNA from 21 MDS patient and 2 AML patients to pooled neutrophil RNA from 7 healthy controls.
2005-01-09 | E-GEOD-971 | biostudies-arrayexpress
Project description:BackgroundMyelodysplastic syndromes (MDS) are characterized by ineffective erythropoiesis with dysplastic bone marrow leading to peripheral cytopenia, risk of infection, and progression to acute myelogenous leukemia. Maitake mushroom beta-glucan, a dietary supplement, stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. This phase II trial examined the effects of Maitake on innate immune function in MDS.MethodsMyelodysplastic syndromes patients with International Prognostic Scoring System Low- and Intermediate-1-risk disease received oral Maitake extract at 3 mg/kg twice daily for 12 weeks. Primary endpoints included neutrophil count and function tested as endogenous or stimulated neutrophil production of reactive oxygen species (ROS) by flow cytometry compared with age-matched healthy controls (HC). ROS activators were Escherichia coli, phorbol ester, and the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Complete blood counts, chemistry panels, iron studies, and monocyte function were evaluated.ResultsOf 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Asymptomatic eosinophilia occurred in 4 patients (p = 0.014). Other changes in albumin, hemoglobin, and total protein were not clinically relevant.ConclusionsMaitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS. Further study is warranted.
| S-EPMC4317517 | biostudies-literature
Project description:A 10K cDNA microarray was used to compare neutrophil RNA from 21 MDS patient and 2 AML patients to pooled neutrophil RNA from 7 healthy controls. Keywords: repeat sample
2005-01-10 | GSE971 | GEO
Project description:The progressive mechanism of myelodysplastic syndrome (MDS) remains unknown. We report that ROBO1 and ROBO2 are identified as novel progression-related somatic mutations using whole-exome and targeted sequencing in six of 16 (37.5%) paired MDS patients undergoing disease progression. To investigated the effect of ROBO1 or ROBO2 on ROBO1/2 CN number and LOH, we employed a Cytosan 750K chip to analyze the copy-number variations (CNVs) and loss of heterogeneity (LOH) in MDS patients with ROBO1&2 mutations. Copy number and LOH analysis of Affymetrix CytoScan 750K array was performed for 14 MDS patients with ROBO1 or ROBO2 mutations
2015-09-15 | E-GEOD-73005 | biostudies-arrayexpress