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DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277889 | GEO | 2025/05/07

REPOSITORIES: GEO

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DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies II

Project description:Primary myelofibrosis (PMF) is a clonal blood disorder linked to mutually exclusive mutations in JAK2, CALR, or MPL genes. To understand the epigenetic effects of these mutations, we analyzed DNA methylation (DNAm) profiles of PMF patients. Notably, no differences were found between JAK2 and CALR mutated cases, whereas MPL mutations showed distinct DNAm patterns. Further investigation in induced pluripotent stem cell (iPSC) models with JAK2 mutations revealed only a moderate link to PMF-related epigenetic changes, suggesting these alterations are not directly caused by the mutations. Additionally, PMF-associated epigenetic changes showed minimal correlation with allele burden and were largely evoked by changes in the cellular composition. When comparing PMF DNAm profiles with those from other myeloid malignancies, such as acute myeloid leukemia, juvenile myelomonocytic leukemia, and myelodysplastic syndrome, many overlapping changes were found, making it difficult to distinguish PMF based on individual CpGs. However, a PMF score created by combining five CpGs successfully differentiated PMF from other diseases in training and validation datasets. These findings demonstrate that PMF driver mutations do not directly evoke epigenetic changes. While PMF shares epigenetic changes with other myeloid malignancies, epigenetic signatures can effectively differentiate PMF from related diseases.

2025-05-07 | GSE277866 | GEO

DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies I

2025-05-07 | GSE277841 | GEO

DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies

Project description:DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies

| PRJNA1164705 | ENA

DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies I

Project description:DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies I

| PRJNA1164666 | ENA

DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies II

Project description:DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies II

| PRJNA1164678 | ENA

Non-driver mutations in myeloproliferative neoplasm-associated myelofibrosis.

Project description:We studied non-driver mutations in 62 subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis upon diagnosis, including 45 subjects with primary myelofibrosis (PMF) and 17 with post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF). Fifty-eight subjects had ≥1 non-driver mutation upon diagnosis. Mutations in mRNA splicing genes, especially in U2AF1, were significantly more frequent in PMF than in post-PV/ET MF (33 vs. 6%; P = 0.015). There were also striking differences in clonal architecture. These data indicate different genomic spectrums between PMF and post-PV/ET MF.

| S-EPMC5414291 | biostudies-literature

Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations.

Project description:This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.

| S-EPMC5533802 | biostudies-literature

Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review.

Project description:Primary myelofibrosis (PMF) is a rare chronic BCR-ABL1-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of PMF include splenomegaly, consequent to extramedullary hematopoiesis, pancytopenias, and an array of potentially debilitating constitutional symptoms. The diagnosis is based on bone marrow morphology and clinical criteria. Mutations in the JAK2 (V617F), MPL (W515), and CALR (exon 9 indel) genes are found in approximately 90% of patients whereas the remaining 10% are so-called triple negatives. Activation of the JAK/STAT pathway results in overproduction of abnormal megakaryocytes leading to bone marrow fibrosis. These mutations might be accompanied by other mutations, such as ASXL1. The commonly used prognostication scoring for PMF is based on the International Prognostic Scoring System. The subsequently developed Dynamic International Prognostic Scoring System-plus employs clinical as well as cytogenetic variables. In PMF, CALR mutation is associated with superior survival and ASXL1 with inferior outcome. Patients with triple-negative PMF have a higher incidence of leukemic transformation and lower overall survival compared with CALR- or JAK2-mutant patients. The impact of genetic lesions on survival is independent of current prognostic scoring systems. These observations indicate that driver and passenger mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

| S-EPMC5588514 | biostudies-literature

Non-driver mutations landscape in different stages of primary myelofibrosis determined ASXL1 mutations play a critical role in disease progression.

Project description: Not available

| S-EPMC10119377 | biostudies-literature

Cohesin mutations in myeloid malignancies.

Project description:Cohesin is a multisubunit protein complex that forms a ring-like structure around DNA. It is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation, and DNA damage repair and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1, and SMC3, as well as its modulators PDS5A/B, WAPL, and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down syndrome-associated acute megakaryoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and de novo and secondary acute myeloid leukemias. The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells, which are associated with changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Herein, we review the role of the cohesin complex in healthy and malignant hematopoiesis. We discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting.

| S-EPMC8394903 | biostudies-literature

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