AML1/ETO oncoprotein is directed to AML1 binding regions and co-localizes with AML1 and HEB on its targets.
A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein.
Gardini
Alessandro
A
Department of Experimental Oncology, IEO-European Institute of Oncology, Milan, Italy.
Cesaroni
Matteo
M
Luzi
Lucilla
L
Okumura
Akiko J
AJ
Biggs
Joseph R
JR
Minardi
Simone P
SP
Venturini
Elisa
E
Zhang
Dong-Er
DE
Pelicci
Pier Giuseppe
PG
Alcalay
Myriam
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000075142:RUNX1 Translocation Partner 1 Protein; D014158:Transcription, Genetic; D020298:U937 Cells
D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C107844:AML1-ETO fusion protein, human; C493728:RUNX1 protein, human; C073366:TCF12 protein, human