TY - JOUR
T1 - RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML
AU - Loke, Justin
AU - Assi, Salam A.
AU - Imperato, Maria Rosaria
AU - Ptasinska, Anetta
AU - Cauchy, Pierre
AU - Grabovska, Yura
AU - Soria, Natalia Martinez
AU - Raghavan, Manoj
AU - Delwel, H. Ruud
AU - Cockerill, Peter N.
AU - Heidenreich, Olaf
AU - Bonifer, Constanze
N1 - Publisher Copyright:
© 2017 The Author(s)
PY - 2017/5/23
Y1 - 2017/5/23
N2 - Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.
AB - Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.
KW - acute myeloid leukemia
KW - chromatin
KW - epigenetic landscape
KW - RUNX1-ETO
KW - RUNX1-EVI1
KW - transcriptional network
UR - http://www.scopus.com/inward/record.url?scp=85019745574&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2017.05.005
DO - 10.1016/j.celrep.2017.05.005
M3 - Article
C2 - 28538183
AN - SCOPUS:85019745574
SN - 2211-1247
VL - 19
SP - 1654
EP - 1668
JO - Cell Reports
JF - Cell Reports
IS - 8
ER -