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 journalArticle

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

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Trombly, D. J., Whitfield, T. W., Padmanabhan, S., Gordon, J. A. R., Lian, J. B., van Wijnen, A. J., Zaidi, S. K., Stein, J. L., & Stein, G. S. (2015). Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells. BMC Genomics, 16(1), [309]. https://doi.org/10.1186/s12864-015-1445-0