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

Author:

Jakobczyk Hélène,Debaize LydieORCID,Soubise Benoit,Avner Stéphane,Rouger-Gaudichon Jérémie,Commet Séverine,Jiang YanORCID,Sérandour Aurélien A.,Rio Anne-Gaëlle,Carroll Jason S.,Wichmann Christian,Lie-a-Ling MichaelORCID,Lacaud GeorgesORCID,Corcos Laurent,Salbert Gilles,Galibert Marie-DominiqueORCID,Gandemer Virginie,Troadec Marie-BérengèreORCID

Abstract

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.

Funder

Ligue Contre le Cancer

Société Française d'hématologie

Région Bretagne

société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent and the Fédération Enfants et Santé

FP7 People: Marie-Curie Actions

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Molecular Biology,Hematology

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