Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations
Abstract Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3A mut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this stud...
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Nature Publishing Group
2025-05-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-025-01287-9 |
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| author | Sao-Chih Ni Chi-Yuan Yao Xavier Cheng-Hong Tsai Min-Yen Lo Chien-Yuan Chen Wan-Hsuan Lee Chien-Chin Lin Yuan-Yeh Kuo Yen-Ling Peng Mei-Hsuan Tseng Yu-Sin Wu Ming-Chih Liu Liang-In Lin Ming-Kai Chuang Bor-Sheng Ko Ming Yao Jih-Luh Tang Feng-Ming Tien Wen-Chien Chou Hsin-An Hou Hwei-Fang Tien |
| author_facet | Sao-Chih Ni Chi-Yuan Yao Xavier Cheng-Hong Tsai Min-Yen Lo Chien-Yuan Chen Wan-Hsuan Lee Chien-Chin Lin Yuan-Yeh Kuo Yen-Ling Peng Mei-Hsuan Tseng Yu-Sin Wu Ming-Chih Liu Liang-In Lin Ming-Kai Chuang Bor-Sheng Ko Ming Yao Jih-Luh Tang Feng-Ming Tien Wen-Chien Chou Hsin-An Hou Hwei-Fang Tien |
| author_sort | Sao-Chih Ni |
| collection | DOAJ |
| description | Abstract Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3A mut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this study, the genomic and transcriptomic features influencing outcomes in DNMT3A-mutated AML were examined in a cohort of 884 patients with AML receiving standard chemotherapy. Stratification by NPM1 and FLT3-ITD status revealed worse survival among patients with NPM1 mutations and wild-type FLT3-ITD (NPM1 mut/FLT3-ITDwt) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1 mut/FLT3-ITDmut, NPM1 wt/FLT3-ITDmut, and NPM1 wt/FLT3-ITDwt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of TET2 mut in patients with AML and DNMT3A mut/NPM1 mut/FLT3-ITDwt led to reclassification from favorable risk to intermediate risk in the ELN-2022. RNA-sequencing analysis revealed a distinct transcriptomic profile in patients with TET2 mut, highlighting the enrichment of leukemic stem cell signatures and dendritic cell migration, with MMP14, CD200, and CT45A5 identified as key differentially expressed genes. In conclusion, co-mutation patterns strongly affected AML outcomes in patients with DNMT3A mut. Patients with TET2 mut constituted a unique subgroup within the ELN-2022 favorable DNMT3A mut/NPM1 mut/FLT3-ITDwt group, characterized by distinct transcriptomic features and an unfavorable prognosis. |
| format | Article |
| id | doaj-art-da3371ec7ab543c482108b94cc3ac5ca |
| institution | Kabale University |
| issn | 2044-5385 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-da3371ec7ab543c482108b94cc3ac5ca2025-08-20T03:48:15ZengNature Publishing GroupBlood Cancer Journal2044-53852025-05-0115111010.1038/s41408-025-01287-9Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutationsSao-Chih Ni0Chi-Yuan Yao1Xavier Cheng-Hong Tsai2Min-Yen Lo3Chien-Yuan Chen4Wan-Hsuan Lee5Chien-Chin Lin6Yuan-Yeh Kuo7Yen-Ling Peng8Mei-Hsuan Tseng9Yu-Sin Wu10Ming-Chih Liu11Liang-In Lin12Ming-Kai Chuang13Bor-Sheng Ko14Ming Yao15Jih-Luh Tang16Feng-Ming Tien17Wen-Chien Chou18Hsin-An Hou19Hwei-Fang Tien20Department of Hematological Oncology, National Taiwan University Cancer CenterDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalGraduate Institute of Clinical Medicine, College of Medicine, National Taiwan UniversityDepartment of Internal Medicine, National Taiwan University Hospital, Hsin-Chu BranchGraduate Institute of Clinical Medicine, College of Medicine, National Taiwan UniversityDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalTai-Chen Cell Therapy Center, National Taiwan UniversityDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalTai-Chen Cell Therapy Center, National Taiwan UniversityDepartment of Nursing, National Taiwan University HospitalDepartment of Pathology, National Taiwan University HospitalDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan UniversityDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalDepartment of Hematological Oncology, National Taiwan University Cancer CenterDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalDepartment of Hematological Oncology, National Taiwan University Cancer CenterDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalDivision of Hematology, Department of Internal Medicine, National Taiwan University HospitalAbstract Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3A mut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this study, the genomic and transcriptomic features influencing outcomes in DNMT3A-mutated AML were examined in a cohort of 884 patients with AML receiving standard chemotherapy. Stratification by NPM1 and FLT3-ITD status revealed worse survival among patients with NPM1 mutations and wild-type FLT3-ITD (NPM1 mut/FLT3-ITDwt) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1 mut/FLT3-ITDmut, NPM1 wt/FLT3-ITDmut, and NPM1 wt/FLT3-ITDwt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of TET2 mut in patients with AML and DNMT3A mut/NPM1 mut/FLT3-ITDwt led to reclassification from favorable risk to intermediate risk in the ELN-2022. RNA-sequencing analysis revealed a distinct transcriptomic profile in patients with TET2 mut, highlighting the enrichment of leukemic stem cell signatures and dendritic cell migration, with MMP14, CD200, and CT45A5 identified as key differentially expressed genes. In conclusion, co-mutation patterns strongly affected AML outcomes in patients with DNMT3A mut. Patients with TET2 mut constituted a unique subgroup within the ELN-2022 favorable DNMT3A mut/NPM1 mut/FLT3-ITDwt group, characterized by distinct transcriptomic features and an unfavorable prognosis.https://doi.org/10.1038/s41408-025-01287-9 |
| spellingShingle | Sao-Chih Ni Chi-Yuan Yao Xavier Cheng-Hong Tsai Min-Yen Lo Chien-Yuan Chen Wan-Hsuan Lee Chien-Chin Lin Yuan-Yeh Kuo Yen-Ling Peng Mei-Hsuan Tseng Yu-Sin Wu Ming-Chih Liu Liang-In Lin Ming-Kai Chuang Bor-Sheng Ko Ming Yao Jih-Luh Tang Feng-Ming Tien Wen-Chien Chou Hsin-An Hou Hwei-Fang Tien Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations Blood Cancer Journal |
| title | Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations |
| title_full | Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations |
| title_fullStr | Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations |
| title_full_unstemmed | Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations |
| title_short | Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations |
| title_sort | genomic and transcriptomic determinants of clinical outcomes in patients with aml and dnmt3a mutations |
| url | https://doi.org/10.1038/s41408-025-01287-9 |
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