Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia

Journal of Hematology & Oncology

卷:14

Jason S. Carroll¹  Georges Lacaud²  Michael Lie-a-Ling²  Christian Wichmann³  Yan Jiang⁴  Benoit Soubise⁴  Séverine Commet⁴  Laurent Corcos⁴  Marie-Dominique Galibert⁵  Gilles Salbert⁵  Jérémie Rouger-Gaudichon⁵  Virginie Gandemer⁵  Lydie Debaize⁵  Marie-Bérengère Troadec⁵  Anne-Gaëlle Rio⁵  Hélène Jakobczyk⁵  Stéphane Avner⁵  Aurélien A. Sérandour⁶ 

[1] Cancer Research UK Cambridge Institute, University of Cambridge;

[2] Cancer Research UK Manchester Institute, University of Manchester;

[3] Department of Transfusion Medicine, Cell Therapeutics and Haemostasis, Ludwig-Maximilians-University of Munich;

[4] Univ Brest, Inserm, EFS, UMR 1078, GGB;

[5] Univ Rennes 1, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290;

[6] Université de Nantes, Ecole Centrale de Nantes, Inserm, CRCINA;

关键词: Childhood leukemia;    RUNX1;    CBFA2T3;    AML1;    ETO2;    Driver loop;   

DOI  :  10.1186/s13045-021-01051-z

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown