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..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2015 |
|---|---|
| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
|---|---|
| Enthalten in: |
BMC genomics - 16(2015), 1 vom: 17. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Trombly, Daniel J [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
AML |
|---|
| Anmerkungen: |
© Trombly et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
|---|
| doi: |
10.1186/s12864-015-1445-0 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
SPR027105202 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR027105202 | ||
| 003 | DE-627 | ||
| 005 | 20230519082510.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 201007s2015 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12864-015-1445-0 |2 doi | |
| 035 | |a (DE-627)SPR027105202 | ||
| 035 | |a (SPR)s12864-015-1445-0-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Trombly, Daniel J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells |
| 264 | 1 | |c 2015 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © Trombly et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( | ||
| 520 | |a 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. | ||
| 650 | 4 | |a AML |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Runx1 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a t(8;21) |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Chromosomal translocation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Myeloid cell differentiation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Epigenetic control |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Whitfield, Troy W |4 aut | |
| 700 | 1 | |a Padmanabhan, Srivatsan |4 aut | |
| 700 | 1 | |a Gordon, Jonathan AR |4 aut | |
| 700 | 1 | |a Lian, Jane B |4 aut | |
| 700 | 1 | |a van Wijnen, Andre J |4 aut | |
| 700 | 1 | |a Zaidi, Sayyed K |4 aut | |
| 700 | 1 | |a Stein, Janet L |4 aut | |
| 700 | 1 | |a Stein, Gary S |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t BMC genomics |d London : BioMed Central, 2000 |g 16(2015), 1 vom: 17. Apr. |w (DE-627)SPR027020185 |w (DE-600)2041499-7 |x 1471-2164 |7 nnns |
| 773 | 1 | 8 | |g volume:16 |g year:2015 |g number:1 |g day:17 |g month:04 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1186/s12864-015-1445-0 |z kostenfrei |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_SPRINGER | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |d 16 |j 2015 |e 1 |b 17 |c 04 | ||