Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein.

Authors:
Yuanyuan Xiao
Yuanyuan Xiao
Kunming Medical University
Epidemiology, Biostatistics
China

PLoS One 2014 4;9(2):e87602. Epub 2014 Feb 4.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.

E2A-PBX1 is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of childhood acute lymphoblastic leukemia. The E2A-PBX1 chimeric transcription factor contains the N-terminal transactivation domain of E2A (TCF3) fused to the C-terminal DNA-binding homeodomain of PBX1. While there is no doubt of its oncogenic potential, the mechanisms of E2A-PBX1-mediated pre-B cell transformation and the nature of direct E2A-PBX1 target genes and pathways remain largely unknown. Herein we used chromatin immunoprecipitation assays (ChIP-chip) to identify direct targets of E2A-PBX1, and we used gene expression arrays of siRNA E2A-PBX1-silenced cells to evaluate changes in expression induced by the fusion protein. Combined ChIP-chip and expression data analysis gave rise to direct and functional targets of E2A-PBX1. Further we observe that the set of ChIP-chip identified E2A-PBX1 targets show a collective down-regulation trend in the E2A-PBX1 silenced samples compared to controls suggesting an activating role of this fusion transcription factor. Our data suggest that the expression of the E2A-PBX1 fusion gene interferes with key regulatory pathways and functions of hematopoietic biology. Among these are members of the WNT and apoptosis/cell cycle control pathways, and thus may comprise an essential driving force for the propagation and maintenance of the leukemic phenotype. These findings may also provide evidence of potentially attractive therapeutic targets.

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913655PMC
December 2014
5 Reads
5 Citations
3.234 Impact Factor

Publication Analysis

Top Keywords

targets e2a-pbx1
12
e2a-pbx1
9
transcription factor
8
fusion protein
8
targets
5
rise direct
4
direct functional
4
functional targets
4
analysis rise
4
expression data
4
combined chip-chip
4
chip-chip expression
4
e2a-pbx1 observe
4
data analysis
4
set chip-chip
4
e2a-pbx1 targets
4
targets collective
4
collective down-regulation
4
trend e2a-pbx1
4
identified e2a-pbx1
4

References

(Supplied by CrossRef)
The role of E2A-PBX1 in leukemogenesis
SE Aspland et al.
Oncogene 2001
Childhood acute lymphoblastic leukemia in the age of genomics
WL Carroll et al.
Pediatr Blood Cancer 2006
E2A-Pbx1 induces growth, blocks differentiation, and interacts with other homeodomain proteins regulating normal differentiation
MP Kamps et al.
Curr Top Microbiol Immunol 1997
The effects of siRNA-mediated inhibition of E2A-PBX1 on EB-1 and Wnt16b expression in the 697 pre-B leukemia cell line
G Casagrande et al.
Haematologica 2006

Similar Publications