Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized variably by the presence of peripheral cytopenias, bone marrow hypercellularity and dysplastic changes in the bone marrow. While MDS patients have an increased risk of progression to acute myeloid leukemia (AML), most MDS patients actually succumb to progressive bone marrow failure. Amongst patients classified as low-risk MDS, different clinical evolutions have been observed, with some patients remaining relatively stable for long periods of time (herein, stable MDS), while others show more progressive disease, with worsening cytopenias, and often increased transfusion requirements (herein, progressive MDS). Current risk stratification strategies fail to distinguish these two groups at diagnosis. We report here that these distinct behaviors are encoded at the epigenetic level and that examining DNA methylation profiles of low-risk MDS patients captures underlying differences between the two different groups. In this study, we identified 356 differentially methylated regions (DMRs) between stable and progressive low-risk MDS at the time of diagnosis. The number of DMRs was almost doubled at the time of progression (681 follow-up DMRs), and this was accompanied by an increase in the local variability at specific methylation regions, and an increase in heterogeneity over time. These findings reveal previously unrecognized epigenetic heterogeneity in low-risk MDS patients and opens the possibility for using epigenetic differences to help improve risk-stratification at diagnosis.

2020-04-14 | GSE108247 | GEO

Sterile alpha motif domain-containing protein 9 is an RNA binding protein impacting ribosome biogenesis and interferon signaling

Project description:Inherited bone marrow failure syndromes often result from pathogenic mutations in genes that are important for ribosome function, namely, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita. Germline mutations in SAMD9 were identified in recent years as a frequent genetic lesion resulting in inherited bone marrow failure and monosomy 7, some patients even have severe multisystem syndromes that include myelodysplasia such as MIRAGE and ataxia-pancytopenia syndromes. The association of germline SAMD9 mutations and bone marrow failure is clear, but to date, there is no reliable method to predict if a novel SAMD9 mutation is pathogenic unless it is accompanied by an obvious family history and/or clinical syndrome. The difficulty with pathogenicity prediction is, in part, due to the incomplete understanding of the biological functions of SAMD9. Here, we used a SAMD9-targeted, inducible CRISPRa/i system to better understand the transcriptional changes that result from SAMD9 transcriptional manipulation. We also used cross-linking and solid phase purification to demonstrate that SAMD9 is an RNA binding protein, and that it is likely through this RNA binding function that SAMD9 affects ribosome biogenesis and subsequently global protein translation and cell proliferation. Thus, ribosome dysfunction contributes to SAMD9-related bone marrow failure like other classical inherited bone marrow failure syndromes.

2025-06-30 | GSE235190 | GEO

Structural genomic variation analysis in patients with bone marrow failure using Illumina Infinium SNP Arrays [Omni1-Quad]

Project description:To better understand the natural history of bone marrow failure syndromes, we analyzed 124 single nucleotide polymorphism arrays (SNP-A) from a comprehensively characterized cohort of 91 patients who had SNP-A for clinical evaluation of BMFS. 67 samples from 51 patients were genotyped with the Quad610, and 57 samples from 54 patients were genotyped with the Omni1-Quad. This submission includes 55 samples from 54 patients that were genotyped with Omni1-Quad. Illumina Infinium SNP-A genotyping was performed on DNA extracted from bone marrow aspirates using standard manufacturer's protocol

2014-01-01 | E-GEOD-48482 | biostudies-arrayexpress

Structural genomic variation analysis in patients with bone marrow failure using Illumina Infinium SNP Arrays [Illumina Quad610 Beadchip]

Project description:To better understand the natural history of bone marrow failure syndromes, we analyzed 124 single nucleotide polymorphism arrays (SNP-A) from a comprehensively characterized cohort of 91 patients who had SNP-A for clinical evaluation of BMFS. 67 samples from 51 patients were genotyped with the Quad610, and 57 samples from 54 patients were genotyped with the Omni1-Quad. This submission includes 67 samples from 51 patients that were genotyped with Illumina Quad610 Beadchip. Illumina Infinium SNP-A genotyping was performed on DNA extracted from bone marrow aspirates using standard manufacturer's protocol

2014-01-01 | E-GEOD-48483 | biostudies-arrayexpress

Gene expression - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. In this study, we analyzed blood samples of 62 AA and 13 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome, Werner syndrome and Hutchinson-Gilford-Progeria syndrome. To gain further insight into the functional relevance of PRDM8 we generated induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, but it did not impact on epigenetic age. Taken together, aberrant DNA methylation in PRDM8 provides a biomarker for bone marrow failure syndromes, which may contribute to the hematopoietic and neuronal phenotypes of premature aging syndromes.

2020-08-31 | GSE141107 | GEO

DNA methylation - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

2020-08-31 | GSE141106 | GEO