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

Published version
Peer-reviewed

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Authors

Jakobczyk, Hélène 
Soubise, Benoit 
Avner, Stéphane 
Rouger-Gaudichon, Jérémie 

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.

Description

Funder: FP7 People: Marie-Curie Actions; doi: http://dx.doi.org/10.13039/100011264; Grant(s): 291851

Keywords

AML1, CBFA2T3, Childhood leukemia, Driver loop, ETO2, Inhibitor, NHR2, RUNX1, Transcription factor, Antineoplastic Agents, Cell Line, Tumor, Child, Core Binding Factor Alpha 2 Subunit, Gene Expression Regulation, Leukemic, Humans, Peptides, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Protein Interaction Domains and Motifs, Protein Interaction Maps, Repressor Proteins, Transcriptional Activation

Journal Title

J Hematol Oncol

Conference Name

Journal ISSN

1756-8722
1756-8722

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
Ligue Contre le Cancer (2017)
Société Française d'hématologie (2017)
Région Bretagne (2016)
société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent and the Fédération Enfants et Santé (2015)