دورية أكاديمية
RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia
| العنوان: | RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia |
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| المؤلفون: | Marion, William, Koppe, Tiago, Chen, Chun-Chin, Wang, Dahai, Frenis, Katie, Fierstein, Sara, Sensharma, Prerana, Aumais, Olivia, Peters, Michael, Ruiz-Torres, Sonya, Chihanga, Tafadzwa, Boettcher, Steffen, Shimamura, Akiko, Bauer, Daniel E, Schlaeger, Thorsten, Wells, Susanne I, Ebert, Benjamin L, Starczynowski, Daniel, da Rocha, Edroaldo Lummertz, Rowe, R Grant |
| المصدر: | Marion, William; Koppe, Tiago; Chen, Chun-Chin; Wang, Dahai; Frenis, Katie; Fierstein, Sara; Sensharma, Prerana; Aumais, Olivia; Peters, Michael; Ruiz-Torres, Sonya; Chihanga, Tafadzwa; Boettcher, Steffen; Shimamura, Akiko; Bauer, Daniel E; Schlaeger, Thorsten; Wells, Susanne I; Ebert, Benjamin L; Starczynowski, Daniel; da Rocha, Edroaldo Lummertz; Rowe, R Grant (2023). RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia. Leukemia, 37(8):1698-1708. |
| بيانات النشر: | Nature Publishing Group |
| سنة النشر: | 2023 |
| المجموعة: | University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| مصطلحات موضوعية: | Clinic for Oncology and Hematology, 610 Medicine & health |
| الوصف: | Many inherited bone marrow failure syndromes (IBMFSs) present a high risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). During transformation of IBMFSs, hematopoietic stem and progenitor cells (HSPCs) with poor fitness gain ectopic, dysregulated self-renewal secondary to somatic mutations via undefined mechanisms. Here, in the context of the prototypical IBMFS Fanconi anemia (FA), we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1 insertions and deletions (indels), generating a model of IBMFS-associated MDS. We observed that compared to the failure state, FA MDS cells show mutant RUNX1-mediated blunting of the G$_{1}$/S cell cycle checkpoint that is normally activated in FA in response to DNA damage. RUNX1 indels also lead to activation of innate immune signaling, which stabilizes the homologous recombination (HR) effector BRCA1, and this pathway can be targeted to abrogate viability and restore sensitivity to genotoxins in FA MDS. Together, these studies develop a paradigm for modeling clonal evolution in IBMFSs, provide basic understanding of the pathogenesis of MDS, and uncover a therapeutic target in FA-associated MDS. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0887-6924 |
| العلاقة: | https://www.zora.uzh.ch/id/eprint/239030/1/s41375_023_01945_6.pdfTest; info:pmid/37391485; urn:issn:0887-6924 |
| DOI: | 10.5167/uzh-239030 |
| DOI: | 10.1038/s41375-023-01945-6 |
| الإتاحة: | https://doi.org/10.5167/uzh-23903010.1038/s41375-023-01945-6Test https://www.zora.uzh.ch/id/eprint/239030Test/ https://www.zora.uzh.ch/id/eprint/239030/1/s41375_023_01945_6.pdfTest |
| حقوق: | info:eu-repo/semantics/closedAccess |
| رقم الانضمام: | edsbas.6DC8A023 |
| قاعدة البيانات: | BASE |
| تدمد: | 08876924 |
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| DOI: | 10.5167/uzh-239030 |