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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2021

Open Access 01-12-2021 | Acute Lymphoblastic Leukemia | Research

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

Authors: 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

Published in: Journal of Hematology & Oncology | Issue 1/2021

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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.
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Metadata
Title
Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia
Authors
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
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2021
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-021-01051-z

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