Department of Cell and Developmental Biology; Program in Bioinformatics and Integrative Biology
Cancer Biology | Cell Biology | Genomics | Hemic and Lymphatic Diseases | Neoplasms
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.
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Citation: BMC Genomics. 2015 Apr 17;16(1):309. doi: 10.1186/s12864-015-1445-0. Link to article on publisher's site
DOI of Published Version
Trombly, Daniel J.; Whitfield, Troy W.; Padmanabhan, Srivatsan; Gordon, Jonathan A. R.; Lian, Jane B.; Van Wijnen, Andre J.; Zaidi, Kaleem; Stein, Janet L.; and Stein, Gary S., "Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells" (2015). Open Access Articles. 2519.
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