KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells
Hypermethylation of tumor suppressor genes is a hallmark of leukemia. The hypomethylating agent decitabine covalently binds, and degrades DNA (cytosine‐5)‐methyltransferase 1 (DNMT1). Structural similarities within DNA‐binding domains of DNMT1, and the leukemic driver histone‐lysine N‐methyltransfer...
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| Format: | Article |
| Language: | English |
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Wiley
2025-05-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13792 |
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| author | Luisa Brock Lina Benzien Sandra Lange Maja Huehns Alexandra Runge Catrin Roolf Anett Sekora Gudrun Knuebel Hugo Murua Escobar Christian Junghanss Anna Richter |
| author_facet | Luisa Brock Lina Benzien Sandra Lange Maja Huehns Alexandra Runge Catrin Roolf Anett Sekora Gudrun Knuebel Hugo Murua Escobar Christian Junghanss Anna Richter |
| author_sort | Luisa Brock |
| collection | DOAJ |
| description | Hypermethylation of tumor suppressor genes is a hallmark of leukemia. The hypomethylating agent decitabine covalently binds, and degrades DNA (cytosine‐5)‐methyltransferase 1 (DNMT1). Structural similarities within DNA‐binding domains of DNMT1, and the leukemic driver histone‐lysine N‐methyltransferase 2A (KMT2A) suggest that decitabine might also affect the latter. In acute lymphoblastic leukemia (ALL) cell lines, and xenograft models, we observed increased DNMT1, and KMT2A expression in response to decitabine‐induced demethylation. Strikingly, KMT2A protein expression was diminished in all cell lines that experienced DNMT1 degradation. Moreover, only cells with reduced KMT2A protein levels showed biological effects following decitabine treatment. KMT2A wild‐type, and rearranged cells were locked in G2 and G1 cell cycle phases, respectively, likely due to p27/p16 activation. Primary sample gene expression profiling confirmed different patterns between KMT2A wild‐type, and translocated cells. This newly discovered decitabine mode of action via KMT2A degradation evokes anti‐leukemic activity in adult ALL cells, and can act synergistically with menin inhibition. Following the successful clinical implementation of decitabine for acute myeloid leukemia, the drug should be considered a potential promising addition to the therapeutic portfolio for ALL as well. |
| format | Article |
| id | doaj-art-97bddb984e144def8111acc976c342e4 |
| institution | DOAJ |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-97bddb984e144def8111acc976c342e42025-08-20T02:58:55ZengWileyMolecular Oncology1574-78911878-02612025-05-011951404142110.1002/1878-0261.13792KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cellsLuisa Brock0Lina Benzien1Sandra Lange2Maja Huehns3Alexandra Runge4Catrin Roolf5Anett Sekora6Gudrun Knuebel7Hugo Murua Escobar8Christian Junghanss9Anna Richter10Department of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyInstitute of Pathology Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine Rostock University Medical Center GermanyHypermethylation of tumor suppressor genes is a hallmark of leukemia. The hypomethylating agent decitabine covalently binds, and degrades DNA (cytosine‐5)‐methyltransferase 1 (DNMT1). Structural similarities within DNA‐binding domains of DNMT1, and the leukemic driver histone‐lysine N‐methyltransferase 2A (KMT2A) suggest that decitabine might also affect the latter. In acute lymphoblastic leukemia (ALL) cell lines, and xenograft models, we observed increased DNMT1, and KMT2A expression in response to decitabine‐induced demethylation. Strikingly, KMT2A protein expression was diminished in all cell lines that experienced DNMT1 degradation. Moreover, only cells with reduced KMT2A protein levels showed biological effects following decitabine treatment. KMT2A wild‐type, and rearranged cells were locked in G2 and G1 cell cycle phases, respectively, likely due to p27/p16 activation. Primary sample gene expression profiling confirmed different patterns between KMT2A wild‐type, and translocated cells. This newly discovered decitabine mode of action via KMT2A degradation evokes anti‐leukemic activity in adult ALL cells, and can act synergistically with menin inhibition. Following the successful clinical implementation of decitabine for acute myeloid leukemia, the drug should be considered a potential promising addition to the therapeutic portfolio for ALL as well.https://doi.org/10.1002/1878-0261.13792acute leukemiadecitabineDNMT1KMT2Ameninrevumenib |
| spellingShingle | Luisa Brock Lina Benzien Sandra Lange Maja Huehns Alexandra Runge Catrin Roolf Anett Sekora Gudrun Knuebel Hugo Murua Escobar Christian Junghanss Anna Richter KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells Molecular Oncology acute leukemia decitabine DNMT1 KMT2A menin revumenib |
| title | KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells |
| title_full | KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells |
| title_fullStr | KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells |
| title_full_unstemmed | KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells |
| title_short | KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells |
| title_sort | kmt2a degradation is observed in decitabine responsive acute lymphoblastic leukemia cells |
| topic | acute leukemia decitabine DNMT1 KMT2A menin revumenib |
| url | https://doi.org/10.1002/1878-0261.13792 |
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