PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis
Background: RUNX1 is a critical transcription factor in hematopoiesis and its mutations occur in various hematological diseases. PHF6 (plant homeodomain finger gene 6) is regarded as an epigenetic modifier, and its mutations are seen in myeloid and lymphoid leukemia. Previous studies have shown posi...
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Elsevier
2025-09-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001809 |
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| author | Yueh-Chwen Hsu Chi-Yuan Yao Chang-Tsu Yuan Chien-Chin Lin Hsin-An Hou Chein-Jun Kao Chia-Lang Hsu Wen-Chien Chou Hwei-Fang Tien |
| author_facet | Yueh-Chwen Hsu Chi-Yuan Yao Chang-Tsu Yuan Chien-Chin Lin Hsin-An Hou Chein-Jun Kao Chia-Lang Hsu Wen-Chien Chou Hwei-Fang Tien |
| author_sort | Yueh-Chwen Hsu |
| collection | DOAJ |
| description | Background: RUNX1 is a critical transcription factor in hematopoiesis and its mutations occur in various hematological diseases. PHF6 (plant homeodomain finger gene 6) is regarded as an epigenetic modifier, and its mutations are seen in myeloid and lymphoid leukemia. Previous studies have shown positive association of these two mutations. However, the joint pathological effects of these two genetic alterations remained unexplored. Methods: We sought to investigate the pathological basis of the association between these two mutations. We first analyzed the clinical, genetic, and transcriptomic features of our cohort of patients with acute myeloid leuemia (AML) focusing on these two mutations. We transduced RUNX1 mutant into the genetically engineered Phf6 knockout (KO) mouse model to generate single- and double-mutated mice for in vivo experiments. Results: In our 1188 adult AML patients, we observed frequent co-occurrence of PHF6 and RUNX1 mutations, and particularly worse clinical outcomes in these double-mutated patients. Double-mutated bone marrow (BM) cells displayed enriched leukemogenesis-related transcriptomic signatures and significantly higher engraftment capacity. The recipient mice transplanted with double-mutated BM cells developed AML with significantly shortened survival. Furthermore, we discovered that the multipotent progenitors (MPPs) were the main cell subpopulation responsible for double-mutated BM cell-induced leukemia. We noted significant up-regulation of high mobility group AT-hook 2 (Hmga2) in double-mutated MPPs and knock-down of Hmga2 abated the self-renewal capacity in vitro.. Conclusions: Our findings highlighted the synergistic leukemogenic potential of Phf6 and RUNX1 mutations in vivo, and provided insights into the molecular mechanisms accounting for this very high-risk disease entity. |
| format | Article |
| id | doaj-art-9013d9a460404e72ad0a5c6f6bcb4e13 |
| institution | OA Journals |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-9013d9a460404e72ad0a5c6f6bcb4e132025-08-20T02:35:19ZengElsevierTranslational Oncology1936-52332025-09-015910244910.1016/j.tranon.2025.102449PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesisYueh-Chwen Hsu0Chi-Yuan Yao1Chang-Tsu Yuan2Chien-Chin Lin3Hsin-An Hou4Chein-Jun Kao5Chia-Lang Hsu6Wen-Chien Chou7Hwei-Fang Tien8Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pathology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, TaiwanDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, TaiwanDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanGraduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, TaiwanDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan; Corresponding author at: Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan S. Rd., Taipei City 10002, Taiwan.Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanBackground: RUNX1 is a critical transcription factor in hematopoiesis and its mutations occur in various hematological diseases. PHF6 (plant homeodomain finger gene 6) is regarded as an epigenetic modifier, and its mutations are seen in myeloid and lymphoid leukemia. Previous studies have shown positive association of these two mutations. However, the joint pathological effects of these two genetic alterations remained unexplored. Methods: We sought to investigate the pathological basis of the association between these two mutations. We first analyzed the clinical, genetic, and transcriptomic features of our cohort of patients with acute myeloid leuemia (AML) focusing on these two mutations. We transduced RUNX1 mutant into the genetically engineered Phf6 knockout (KO) mouse model to generate single- and double-mutated mice for in vivo experiments. Results: In our 1188 adult AML patients, we observed frequent co-occurrence of PHF6 and RUNX1 mutations, and particularly worse clinical outcomes in these double-mutated patients. Double-mutated bone marrow (BM) cells displayed enriched leukemogenesis-related transcriptomic signatures and significantly higher engraftment capacity. The recipient mice transplanted with double-mutated BM cells developed AML with significantly shortened survival. Furthermore, we discovered that the multipotent progenitors (MPPs) were the main cell subpopulation responsible for double-mutated BM cell-induced leukemia. We noted significant up-regulation of high mobility group AT-hook 2 (Hmga2) in double-mutated MPPs and knock-down of Hmga2 abated the self-renewal capacity in vitro.. Conclusions: Our findings highlighted the synergistic leukemogenic potential of Phf6 and RUNX1 mutations in vivo, and provided insights into the molecular mechanisms accounting for this very high-risk disease entity.http://www.sciencedirect.com/science/article/pii/S1936523325001809Acute myeloid leukemiaPHF6, RUNX1Leukemia stem cellHmga2 |
| spellingShingle | Yueh-Chwen Hsu Chi-Yuan Yao Chang-Tsu Yuan Chien-Chin Lin Hsin-An Hou Chein-Jun Kao Chia-Lang Hsu Wen-Chien Chou Hwei-Fang Tien PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis Translational Oncology Acute myeloid leukemia PHF6, RUNX1 Leukemia stem cell Hmga2 |
| title | PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis |
| title_full | PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis |
| title_fullStr | PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis |
| title_full_unstemmed | PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis |
| title_short | PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis |
| title_sort | phf6 and runx1 mutations cooperate to accelerate leukemogenesis |
| topic | Acute myeloid leukemia PHF6, RUNX1 Leukemia stem cell Hmga2 |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001809 |
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