Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells

Daniel J. Trombly, Troy W. Whitfield, Srivatsan Padmanabhan, Jonathan A.R. Gordon, Jane B. Lian, Andre J. van Wijnen, Sayyed K. Zaidi, Janet L. Stein, Gary S. Stein

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background: Many leukemias result from chromosomal rearrangements. The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for myeloid cell differentiation. Because of the pressing need for new therapies in the treatment of acute myleoid leukemia, we investigated the genome-wide occupancy of AML1-ETO in leukemic cells to discover novel regulatory mechanisms involving AML-ETO bound genes. Results: We report the co-localization of AML1-ETO with the N-CoR co-repressor to be primarily on genomic regions distal to transcriptional start sites (TSSs). These regions exhibit over-representation of the motif for PU.1, a key hematopoietic regulator and member of the ETS family of transcription factors. A significant discovery of our study is that genes co-occupied by AML1-ETO and N-CoR (e.g., TYROBP and LAPTM5) are associated with the leukemic phenotype, as determined by analyses of gene ontology and by the observation that these genes are predominantly up-regulated upon AML1-ETO depletion. In contrast, the AML1-ETO/p300 gene network is less responsive to AML1-ETO depletion and less associated with the differentiation block characteristic of leukemic cells. Furthermore, a substantial fraction of AML1-ETO/p300 co-localization occurs near TSSs in promoter regions associated with transcriptionally active loci. Conclusions: Our findings establish a novel and dominant t(8;21) AML leukemia signature characterized by occupancy of AML1-ETO/N-CoR at promoter-distal genomic regions enriched in motifs for myeloid differentiation factors, thus providing mechanistic insight into the leukemic phenotype.

Original languageEnglish (US)
Article number309
JournalBMC genomics
Volume16
Issue number1
DOIs
StatePublished - Dec 12 2015

Keywords

  • AML
  • Chromosomal translocation
  • Epigenetic control
  • Myeloid cell differentiation
  • Runx1
  • t(8;21)

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Fingerprint Dive into the research topics of 'Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells'. Together they form a unique fingerprint.

Cite this