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

Journal of Hematology & Oncology

Jason S. Carroll¹  Georges Lacaud²  Michael Lie-a-Ling²  Christian Wichmann³  Benoit Soubise⁴  Laurent Corcos⁴  Séverine Commet⁵  Yan Jiang⁶  Hélène Jakobczyk⁷  Stéphane Avner⁷  Gilles Salbert⁷  Anne-Gaëlle Rio⁷  Lydie Debaize⁷  Virginie Gandemer⁸  Jérémie Rouger-Gaudichon⁹  Marie-Dominique Galibert^1,10  Marie-Bérengère Troadec^1,11  Aurélien A. Sérandour^1,12 

[1] Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE, Cambridge, UK;Cancer Research UK Manchester Institute, University of Manchester, Aderley Park, SK10 4TG, Macclesfield, UK;Department of Transfusion Medicine, Cell Therapeutics and Haemostasis, Ludwig-Maximilians-University of Munich, Munich, Germany;Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200, Brest, France;Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200, Brest, France;CHRU Brest, Service de génétique, laboratoire de génétique chromosomique, 22 avenue Camille Desmoulins, 29238, Brest Cedex 3, France;Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200, Brest, France;Department of Hematology, The First Hospital of Jilin University, Changchun, China;Univ Rennes 1, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, 35000, Rennes, France;Univ Rennes 1, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, 35000, Rennes, France;Department of Pediatric Hemato-Oncology, Centre Hospitalier Universitaire de Rennes (CHU-Rennes), 35203, Rennes, France;Univ Rennes 1, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, 35000, Rennes, France;Département d’onco-hematologie pediatrique, Centre Hospitalier Universitaire de Caen Normandie, Caen, France;Univ Rennes 1, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, 35000, Rennes, France;Service de Génétique et Génomique Moléculaire, Centre Hospitalier Universitaire de Rennes (CHU-Rennes), 35033, Rennes, France;Univ Rennes 1, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, 35000, Rennes, France;Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200, Brest, France;CHRU Brest, Service de génétique, laboratoire de génétique chromosomique, 22 avenue Camille Desmoulins, 29238, Brest Cedex 3, France;Université de Nantes, Ecole Centrale de Nantes, Inserm, CRCINA, Nantes, France;

关键词: Childhood leukemia;    RUNX1;    CBFA2T3;    AML1;    ETO2;    Driver loop;    Transcription factor;    NHR2;    Inhibitor;   

DOI  :  10.1186/s13045-021-01051-z

来源: Springer

【 摘 要 】

BackgroundB 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.MethodsWe 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.ResultsWe 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.ConclusionsAltogether, 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】

CC BY