Tumor suppressor BTG1 limits activation of BCL6 expression downstream of ETV6-RUNX1

Esther Tijchon, Liesbeth van Emst, Laurensia Yuniati, Dorette van Ingen Schenau, Mylène Gerritsen, Laurens T van der Meer, Owen Williams, Peter M Hoogerbrugge, Blanca Scheijen, Frank N van Leeuwen

Research output: Contribution to journalArticlepeer-review

Abstract

Translocation t(12;21) (p13;q22), giving rise to the ETV6-RUNX1 fusion gene, is the most common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation usually arises in utero, but its expression is insufficient to induce leukemia and requires other cooperating genetic lesions for BCP-ALL to develop. Deletions affecting the transcriptional coregulator BTG1 are frequently observed in ETV6-RUNX1-positive leukemia. Here we report that Btg1 deficiency enhances the self-renewal capacity of ETV6-RUNX1-positive mouse fetal liver-derived hematopoietic progenitors (FL-HPCs). Combined expression of the fusion protein and a loss of BTG1 drive upregulation of the proto-oncogene Bcl6 and downregulation of BCL6 target genes, such as p19Arf and Tp53. Similarly, ectopic expression of BCL6 promotes the self-renewal and clonogenic replating capacity of FL-HPCs, by suppressing the expression of p19Arf and Tp53. Together these results identify BCL6 as a potential driver of ETV6-RUNX1-mediated leukemogenesis, which could involve loss of BTG1-dependent suppression of ETV6-RUNX1 function.

Original languageEnglish
Pages (from-to)57-62.e3
JournalExperimental hematology
Volume60
DOIs
Publication statusPublished - Apr 2018

Keywords

  • Animals
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Cyclin-Dependent Kinase Inhibitor p16
  • Gene Expression Regulation, Leukemic
  • Leukemia/genetics
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins/genetics
  • Oncogene Proteins, Fusion/genetics
  • Proto-Oncogene Proteins c-bcl-6/biosynthesis
  • Proto-Oncogene Proteins c-ets/genetics
  • Repressor Proteins/genetics
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins/genetics

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