دورية أكاديمية
Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias
| العنوان: | Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias |
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| المؤلفون: | Nishida, Yuki, Ishizawa, Jo, Ayoub, Edward, Montoya, Rafael Heinz, Ostermann, Lauren B, Muftuoglu, Muharrem, Ruvolo, Vivian R, Patsilevas, Tallie, Scruggs, Darah A, Khazaei, Shayaun, Mak, Po Yee, Tao, Wenjing, Carter, Bing Z, Boettcher, Steffen, Ebert, Benjamin L, Daver, Naval G, Konopleva, Marina, Seki, Takahiko, Kojima, Kensuke, Andreeff, Michael |
| المصدر: | Nishida, Yuki; Ishizawa, Jo; Ayoub, Edward; Montoya, Rafael Heinz; Ostermann, Lauren B; Muftuoglu, Muharrem; Ruvolo, Vivian R; Patsilevas, Tallie; Scruggs, Darah A; Khazaei, Shayaun; Mak, Po Yee; Tao, Wenjing; Carter, Bing Z; Boettcher, Steffen; Ebert, Benjamin L; Daver, Naval G; Konopleva, Marina; Seki, Takahiko; Kojima, Kensuke; Andreeff, Michael (2023). Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias. Science Advances, 9(48):eadh1436. |
| بيانات النشر: | American Association for the Advancement of Science |
| 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: | The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2375-2548 |
| العلاقة: | https://www.zora.uzh.ch/id/eprint/251944/1/sciadv.adh1436.pdfTest; info:pmid/38019903; urn:issn:2375-2548 |
| DOI: | 10.5167/uzh-251944 |
| DOI: | 10.1126/sciadv.adh1436 |
| الإتاحة: | https://doi.org/10.5167/uzh-25194410.1126/sciadv.adh1436Test https://www.zora.uzh.ch/id/eprint/251944Test/ https://www.zora.uzh.ch/id/eprint/251944/1/sciadv.adh1436.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess ; Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) ; http://creativecommons.org/licenses/by-nc/4.0Test/ |
| رقم الانضمام: | edsbas.60C1143D |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23752548 |
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| DOI: | 10.5167/uzh-251944 |