TY - JOUR
T1 - Tumor suppressor BTG1 limits activation of BCL6 expression downstream of ETV6-RUNX1
AU - Tijchon, Esther
AU - van Emst, Liesbeth
AU - Yuniati, Laurensia
AU - van Ingen Schenau, Dorette
AU - Gerritsen, Mylène
AU - van der Meer, Laurens T
AU - Williams, Owen
AU - Hoogerbrugge, Peter M
AU - Scheijen, Blanca
AU - van Leeuwen, Frank N
N1 - Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - Animals
KW - Core Binding Factor Alpha 2 Subunit/genetics
KW - Cyclin-Dependent Kinase Inhibitor p16
KW - Gene Expression Regulation, Leukemic
KW - Leukemia/genetics
KW - Mice
KW - Mice, Knockout
KW - Neoplasm Proteins/genetics
KW - Oncogene Proteins, Fusion/genetics
KW - Proto-Oncogene Proteins c-bcl-6/biosynthesis
KW - Proto-Oncogene Proteins c-ets/genetics
KW - Repressor Proteins/genetics
KW - Tumor Suppressor Protein p53
KW - Tumor Suppressor Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85042009988&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2018.01.006
DO - 10.1016/j.exphem.2018.01.006
M3 - Article
C2 - 29408281
SN - 0301-472X
VL - 60
SP - 57-62.e3
JO - Experimental hematology
JF - Experimental hematology
ER -