دورية أكاديمية
Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia
| العنوان: | Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia |
|---|---|
| المؤلفون: | Hélène Jakobczyk, Lydie Debaize, Benoit Soubise, Stéphane Avner, Jérémie Rouger-Gaudichon, Séverine Commet, Yan Jiang, Aurélien A. Sérandour, Anne-Gaëlle Rio, Jason S. Carroll, Christian Wichmann, Michael Lie-a-Ling, Georges Lacaud, Laurent Corcos, Gilles Salbert, Marie-Dominique Galibert, Virginie Gandemer, Marie-Bérengère Troadec |
| المصدر: | Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-17 (2021) |
| بيانات النشر: | BMC, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Childhood leukemia, RUNX1, CBFA2T3, AML1, ETO2, Driver loop, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Abstract Background B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) is the most common pediatric cancer. Identifying key players involved in proliferation of BCP-ALL cells is crucial to propose new therapeutic targets. Runt Related Transcription Factor 1 (RUNX1) and Core-Binding Factor Runt Domain Alpha Subunit 2 Translocated To 3 (CBFA2T3, ETO2, MTG16) are master regulators of hematopoiesis and are implicated in leukemia. Methods We worked with BCP-ALL mononuclear bone marrow patients’ cells and BCP-ALL cell lines, and performed Chromatin Immunoprecipitations followed by Sequencing (ChIP-Seq), co-immunoprecipitations (co-IP), proximity ligation assays (PLA), luciferase reporter assays and mouse xenograft models. Results We demonstrated that CBFA2T3 transcript levels correlate with RUNX1 expression in the pediatric t(12;21) ETV6-RUNX1 BCP-ALL. By ChIP-Seq in BCP-ALL patients’ cells and cell lines, we found that RUNX1 is recruited on its promoter and on an enhancer of CBFA2T3 located − 2 kb upstream CBFA2T3 promoter and that, subsequently, the transcription factor RUNX1 drives both RUNX1 and CBFA2T3 expression. We demonstrated that, mechanistically, RUNX1 and CBFA2T3 can be part of the same complex allowing CBFA2T3 to strongly potentiate the activity of the transcription factor RUNX1. Finally, we characterized a CBFA2T3-mimicking peptide that inhibits the interaction between RUNX1 and CBFA2T3, abrogating the activity of this transcription complex and reducing BCP-ALL lymphoblast proliferation. Conclusions Altogether, our findings reveal a novel and important activation loop between the transcription regulator CBFA2T3 and the transcription factor RUNX1 that promotes BCP-ALL proliferation, supporting the development of an innovative therapeutic approach based on the NHR2 subdomain of CBFA2T3 protein. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1756-8722 |
| Relation: | https://doaj.org/toc/1756-8722 |
| DOI: | 10.1186/s13045-021-01051-z |
| URL الوصول: | https://doaj.org/article/3e5be24cee0f4d4db6d0258b58f9a08b |
| رقم الأكسشن: | edsdoj.3e5be24cee0f4d4db6d0258b58f9a08b |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 17568722 |
|---|---|
| DOI: | 10.1186/s13045-021-01051-z |