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Molecule | Function of the molecule | Structure: mechanism of interaction | Function/biological effect |
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Molecular interaction with the fusion molecule as a partner molecules |
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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 |
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Modulation of the fusion molecule |
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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 |
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