DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies
Abstract Background Primary myelofibrosis (PMF) is a clonal blood disorder characterized by mutually exclusive driver mutations in JAK2, CALR, or MPL genes. So far, it is largely unclear if the driver mutations have a specific impact on DNA methylation (DNAm) profiles and how epigenetic alterations...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13148-025-01877-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850042786924986368 |
|---|---|
| author | Esra Dursun Torlak Vithurithra Tharmapalan Kim Kricheldorf Joelle Schifflers Madeline Caduc Martin Zenke Steffen Koschmieder Wolfgang Wagner |
| author_facet | Esra Dursun Torlak Vithurithra Tharmapalan Kim Kricheldorf Joelle Schifflers Madeline Caduc Martin Zenke Steffen Koschmieder Wolfgang Wagner |
| author_sort | Esra Dursun Torlak |
| collection | DOAJ |
| description | Abstract Background Primary myelofibrosis (PMF) is a clonal blood disorder characterized by mutually exclusive driver mutations in JAK2, CALR, or MPL genes. So far, it is largely unclear if the driver mutations have a specific impact on DNA methylation (DNAm) profiles and how epigenetic alterations in PMF are related to other myeloid malignancies. Results When we compared DNAm profiles from PMF patients we found very similar epigenetic modifications in JAK2 and CALR mutated cases, whereas MPL mutations displayed less pronounced and distinct patterns. Furthermore, induced pluripotent stem cell (iPSC) models with JAK2 mutations indicated only a moderate association with PMF-related epigenetic changes, suggesting that these alterations may not be directly driven by the mutations themselves. Additionally, PMF-associated epigenetic changes showed minimal correlation with allele burden and seemed to be largely influenced by shifts in the cellular composition. PMF DNAm profiles compared with those from other myeloid malignancies—such as acute myeloid leukemia, juvenile myelomonocytic leukemia, and myelodysplastic syndrome—showed numerous overlapping changes, making it difficult to distinguish PMF based on individual CpGs. However, a PMF score created by combining five CpGs was able to discern PMF from other diseases. Conclusion These findings demonstrate that PMF driver mutations do not directly evoke epigenetic changes. While PMF shares epigenetic alterations with other myeloid malignancies, DNA methylation patterns can distinguish between PMF and related diseases. |
| format | Article |
| id | doaj-art-71d93076c7ab45718e4c27639b26ae92 |
| institution | DOAJ |
| issn | 1868-7083 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj-art-71d93076c7ab45718e4c27639b26ae922025-08-20T02:55:27ZengBMCClinical Epigenetics1868-70832025-05-0117111310.1186/s13148-025-01877-1DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignanciesEsra Dursun Torlak0Vithurithra Tharmapalan1Kim Kricheldorf2Joelle Schifflers3Madeline Caduc4Martin Zenke5Steffen Koschmieder6Wolfgang Wagner7Institute for Stem Cell Biology, RWTH Aachen University Medical SchoolInstitute for Stem Cell Biology, RWTH Aachen University Medical SchoolDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of RWTH Aachen University, University Hospital AachenDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of RWTH Aachen University, University Hospital AachenDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of RWTH Aachen University, University Hospital AachenHelmholtz-Institute for Biomedical Engineering, RWTH Aachen University Medical SchoolDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of RWTH Aachen University, University Hospital AachenInstitute for Stem Cell Biology, RWTH Aachen University Medical SchoolAbstract Background Primary myelofibrosis (PMF) is a clonal blood disorder characterized by mutually exclusive driver mutations in JAK2, CALR, or MPL genes. So far, it is largely unclear if the driver mutations have a specific impact on DNA methylation (DNAm) profiles and how epigenetic alterations in PMF are related to other myeloid malignancies. Results When we compared DNAm profiles from PMF patients we found very similar epigenetic modifications in JAK2 and CALR mutated cases, whereas MPL mutations displayed less pronounced and distinct patterns. Furthermore, induced pluripotent stem cell (iPSC) models with JAK2 mutations indicated only a moderate association with PMF-related epigenetic changes, suggesting that these alterations may not be directly driven by the mutations themselves. Additionally, PMF-associated epigenetic changes showed minimal correlation with allele burden and seemed to be largely influenced by shifts in the cellular composition. PMF DNAm profiles compared with those from other myeloid malignancies—such as acute myeloid leukemia, juvenile myelomonocytic leukemia, and myelodysplastic syndrome—showed numerous overlapping changes, making it difficult to distinguish PMF based on individual CpGs. However, a PMF score created by combining five CpGs was able to discern PMF from other diseases. Conclusion These findings demonstrate that PMF driver mutations do not directly evoke epigenetic changes. While PMF shares epigenetic alterations with other myeloid malignancies, DNA methylation patterns can distinguish between PMF and related diseases.https://doi.org/10.1186/s13148-025-01877-1Primary myelofibrosisDNA methylationMyeloid malignanciesMPNAMLJMML |
| spellingShingle | Esra Dursun Torlak Vithurithra Tharmapalan Kim Kricheldorf Joelle Schifflers Madeline Caduc Martin Zenke Steffen Koschmieder Wolfgang Wagner DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies Clinical Epigenetics Primary myelofibrosis DNA methylation Myeloid malignancies MPN AML JMML |
| title | DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies |
| title_full | DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies |
| title_fullStr | DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies |
| title_full_unstemmed | DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies |
| title_short | DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies |
| title_sort | dna methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies |
| topic | Primary myelofibrosis DNA methylation Myeloid malignancies MPN AML JMML |
| url | https://doi.org/10.1186/s13148-025-01877-1 |
| work_keys_str_mv | AT esradursuntorlak dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT vithurithratharmapalan dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT kimkricheldorf dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT joelleschifflers dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT madelinecaduc dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT martinzenke dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT steffenkoschmieder dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies AT wolfgangwagner dnamethylationinprimarymyelofibrosisispartlyassociatedwithdrivermutationsanddistinctfromothermyeloidmalignancies |