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Jakobczyk, Hélène; Debaize, Lydie; Soubise, Benoit; Avner, Stéphane; Rouger-Gaudichon, Jérémie; Commet, Séverine; Jiang, Yan; Sérandour, Aurélien A.; Rio, Anne-Gaëlle; Carroll, Jason S.; Wichmann, Christian; Lie-a-Ling, Michael; Lacaud, Georges; Corcos, Laurent; Salbert, Gilles; Galibert, Marie-Dominique; Gandemer, Virginie; Troadec, Marie-Bérengère

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

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  • Media type: E-Article
  • Title: Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia
  • Contributor: Jakobczyk, Hélène; Debaize, Lydie; Soubise, Benoit; Avner, Stéphane; Rouger-Gaudichon, Jérémie; Commet, Séverine; Jiang, Yan; Sérandour, Aurélien A.; Rio, Anne-Gaëlle; Carroll, Jason S.; Wichmann, Christian; Lie-a-Ling, Michael; Lacaud, Georges; Corcos, Laurent; Salbert, Gilles; Galibert, Marie-Dominique; Gandemer, Virginie; Troadec, Marie-Bérengère
  • imprint: Springer Science and Business Media LLC, 2021
  • Published in: Journal of Hematology & Oncology
  • Language: English
  • DOI: 10.1186/s13045-021-01051-z
  • ISSN: 1756-8722
  • Keywords: Cancer Research ; Oncology ; Molecular Biology ; Hematology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We demonstrated that <jats:italic>CBFA2T3</jats:italic> transcript levels correlate with <jats:italic>RUNX1</jats:italic> expression in the pediatric t(12;21) <jats:italic>ETV6-RUNX1</jats:italic> 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 <jats:italic>CBFA2T3</jats:italic> located − 2 kb upstream <jats:italic>CBFA2T3</jats:italic> promoter and that, subsequently, the transcription factor RUNX1 drives both <jats:italic>RUNX1</jats:italic> and <jats:italic>CBFA2T3</jats:italic> 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.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>
  • Access State: Open Access