Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO

Abstract

Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the corepressors N-CoR and SMRT and recruits HDAC in vivo. The fusion protein AML1-ETO retains the ability of ETO to form stable complexes with N-CoR/SMRT and HDAC. Deletion of the ETO C terminus abolishes CoR binding and HDAC recruitment and severely impairs the ability of AML1-ETO to inhibit differentiation of hematopoietic precursors. These data indicate that formation of a stable complex with CoR-HDAC is crucial to the activation of the leukemogenic potential of AML1 by ETO and suggest that aberrant recruitment of corepressor complexes is a general mechanism of leukemogenesis.

The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoR

“…The MYND domain is essential for BS69 repression (Figure 3), presumably via recruitment of N-CoR and possibly SMRT containing complexes. Although we have not yet been able to test SMRT binding to BS69, the MYND domain of AML/ETO fusion protein does interact with SMRT (Gelmetti et al, 1998) suggesting that BS69 will also be able to associate with SMRT. A Figure 5 The N-terminal domains of BS69 are required for mediating repression.…”

“…Since the MYND domain is a putative interaction molecule for the nuclear co-repressors N-CoR and SMRT (Lutterbach et al, 1998a;Gelmetti et al, 1998;Wang et al, 1998) we tested whether the MYND domain of BS69 also mediates N-CoR binding in a coimmunoprecipitation experiment. We transfected human U2OS osteosarcoma cells with expression vectors for FLAG tagged N-CoR and full-length human BS69 fused to the DNA binding domain of the yeast transcription factor GAL4 at the N-terminus ( Figure 2).…”

“…The C-terminus harbours a region with homology to the MYND domain, a two zinc ®nger motif ®rst identi®ed in DEAF-1 (Gross and McGinnis, 1996) and in MTG8/ETO (Lutterbach et al, 1998a). This domain was shown to be required for both repression of basal transcription by the AML/ETO fusion protein and binding of the transcriptional corepressors N-CoR and SMRT (Lutterbach et al, 1998b;Gelmetti et al, 1998;Wang et al, 1998). N-CoR and its close homologue SMRT were cloned as co-repressors of the thyroidhormone and retinoic acid receptors (Chen and Evans, 1995;Horlein et al, 1995).…”

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

“…The resulting AML1-ETO fusion protein is expressed in E12% of AML of the M2 subtype (Look, 1997). AML1-ETO has been shown to interact with a number of proteins present in corepressor complexes, suggesting that AML1-ETO may act as a transcriptional repressor (Meyers et al, 1995;Gelmetti et al, 1998;Lutterbach et al, 1998;Wang et al, 1998;Westendorf et al, 1998;Amann et al, 2001;Hildebrand et al, 2001;Zhang et al, 2001;Linggi et al, 2002;Lausen et al, 2004). However, there have been very few studies that correlate a DNA binding event by AML1-ETO at a target gene's promoter with a direct consequence on transcription (see, e.g.…”

True

“…1,2,4 The ETO moiety of the t(8;21) translocation has recently been shown to recruit the transcriptional repressor complex, thereby repressing transcription from genes normally activated by AML1. 4 In contrast, fusions involving MLL on chromosome 11q23, and translocations and inversions involving CBP on chromosome 8 (such as the t(8;16), t(11;16), and inv(8)) appear to interfere with recruitment of the transcriptional activator complex and ACTR (Figure 3). Thus, transcription regulation is very complex and different leukemia genotypes may impact different components of these regulatory pathways.…”