Table 3.

Important proteins that directly interact with or modulate the t(8;21) fusion protein.

Molecule	Function of the molecule	Structure: mechanism of interaction	Function/biological effect
Molecular interaction with the fusion molecule as a partner molecules
GFI1 [71]	Transcription repressor	GF35N and GF36S variant alleles have repressor activity. The fusion protein colocalizes and interacts with the more common GFI136S, and its repressor activity is thereby inhibited; the fusion protein does not colocalize or inhibit the GFI135N repressor activity	GFI1 is a regulator of myeloid differentiation, and the interaction and effect of the fusion protein vary between patients and depend on genetic differences
CBPβ [72]	Transcription repressor	Forms heterodimers with the t(8;21) fusion protein through binding to the Runt domain from AML1/RUNX1	Animal models suggest that CBPβ is important for contribution to the fusion proteins inhibition of neutrophil differentiation, is essential for its growth-enhancing effect and cooperation with receptor-initiated signaling
E-proteins [60]	Transcription factor	DNA-bound E-proteins interact with the histone acetyl transferase p300/CREB binding protein, leading to histone acetylation and initiation of transcription. This effect is silenced by the fusion protein through (i) preventing E-protein/p300 activation and (ii) local recruitment of HDACs	E-proteins are important regulators of growth, differentiation and apoptosis and these functions are probably inhibited through a stable binding to the NHR4 domain of the fusion protein
SMRT/N-CoR complex [73]	Transcriptional regulators	Binding of the complex together with their associated HDACs to AML1 target genes through the fusion protein causes aberrant repression of transcription	Contributes to the differentiation block and attenuates the effect of the fusion protein on cell proliferation
UBF1 [74]	Transcription factor	UBF1 binds ribosomal DNA and regulates RNA polymerase 1 activity (see below); the fusion protein associates with UBF1	Modulation of RNA polymerase 1-mediated ribosomal RNA transcription during interphase
SON [75]	Growth regulation	Binding to the NHR4 domain and is possibly involved in the antiproliferative signaling mediated by this domain	SON shows an abnormal cytoplasmic localization in t(8;21) cells; the functions are largely unknown but it seems to be involved in regulation of proliferation and apoptosis
Histone deacetylases [73]	Acetylation of histones	Direct recruitment of HDACs with silencing of AML1-target hematopoietic genes	There is physical binding between the fusion protein and HDAC1, the final functional effect being regarded as a leukemia-enhancing effect
DNA methyltransferase 1 [76]	DNA methylation	Silencing of gene expression through methylation, probably functionally linked to HDACs.	Contributes to the silencing of gene expression, and is involved in the reduced IL3 expression
Protein kinase A (PKA) [78]	Protein phosphorylation	Binding to the NHR-3 domain of the fusion protein	Even though PKA is important for regulation of cell proliferation, the interaction with AML1-ETO does not seem to have any major impact on proliferation or in vivo leukemogenesis
Modulation of the fusion molecule
Calpains [77]	Proteolytic cleavage	Calpain is required for the induction of blood disorders by the fusion protein in Drosophilia	Calpains cleave a restricted set of protein substrates; one hypothesis is that the enzyme cleaves the fusion protein, and thereby generates a more potent inducer of leukemia similar to the leukemic splice variant. Alternatively calpains may affect leukemic cell migration
Alternative AML1/ETO splicing [62]		One of the splice variants lacks the two carboxyterminal ETO domains	In contrast to the full-length variant this alternatively spliced molecule alone can induce leukemic transformation in experimental models without additional genetic abnormalities