Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells.
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.
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. daniel.trombly@umassmed.edu.
Daniel J
DJ
Trombly
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. troy.whitfield@umassmed.edu.|Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. troy.whitfield@umassmed.edu.
Troy W
TW
Whitfield
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. psrivats@yahoo.com.
Srivatsan
S
Padmanabhan
Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA. jonathan.a.gordon@uvm.edu.|Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. jonathan.a.gordon@uvm.edu.
Jonathan A R
JA
Gordon
Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA. jane.lian@uvm.edu.|Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. jane.lian@uvm.edu.
Jane B
JB
Lian
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. vanwijnen.andre@mayo.edu.|Current address: Biomedical Sciences, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. vanwijnen.andre@mayo.edu.
Andre J
AJ
van Wijnen
Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA. sayyed.zaidi@uvm.edu.|Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. sayyed.zaidi@uvm.edu.
Sayyed K
SK
Zaidi
Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA. janet.stein@uvm.edu.|Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. janet.stein@uvm.edu.
Janet L
JL
Stein
Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA. gary.stein@uvm.edu.|Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. gary.stein@uvm.edu.
Gary S
GS
Stein
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000075142:RUNX1 Translocation Partner 1 Protein; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human