|
| Molecule | Function | Effect of AML1/ETO on the molecule | Final effect on t(8;21) cells |
|
| Altered gene transcription |
|
| PU.1 [82] | Transcription factor | Decreased expression by AML1/ETO | Inhibition of differentiation |
|
| C/EBPα [83, 84] | Transcription factor | Downregulation of C/EBPα; the normal function of this factor is regulation of differentiation and inhibition of proliferation | Increased proliferation and inhibition of differentiation |
|
| C/EBP β [85] | Transcription factor | The normal function is transcriptional upregulation of C/EBPα | Altered regulation of differentiation and proliferation through reduced expression of C/EBPα |
|
| POU4F1 [86] | Transcription factor | The POU4F1 levels are significantly correlated with the fusion protein levels. One study described differential regulation of 140 genes by this factor, and half of them are also AML1/ETO targets | POU4F1 probably contribute to the gene expression signature associated with t(8;21) AML |
|
| PAX5 [87, 88] | Transcription factor | Increased expression at the mRNA and protein level | Aberrant expression of B lymphocyte markers, including CD19, CD79a |
|
| RNA-rependent mechanisms and ribosomal functions |
|
| μRNA [62, 89] | Regulatory RNA molecules | The fusion protein selects a set of μRNAs (miR); it occupies the miR-24-23-27 locus and upregulates their expression | Modulation of proliferation and differentiation through the effects on miR24 |
| miR24 downregulates the mitogen-activated protein kinase phosphatase 7 and enhances the downstream signaling through phosphorylation of c-jun and p38 kinases |
| Silencing of miR223 through epigenetic mechanisms | Altered regulation of myelopoiesis through effects on mir223 |
|
| RNA polymerase I [74] | Transcriptional regulators | The fusion protein seems to localize to the nucleolar organizing regions during mitosis, associates with metaphase chromosomes and occupies ribosomal DNA repeats during interphase together with UBF1 (see Table 3) | In contrast to AML1 the fusion protein seems to be a positive regulator of rDNA transcription. Transcription regulated by RNA polymerase 1 seems to increase the proliferation of transformed cells (discussed in [74]) |
|
| DNA damage and repair |
|
| OGG1[20] | DNA repair | OGG1 is an important part of the DNA base excision repair pathway, its expression is downregulated by the fusion protein | High OGG1 levels are associated with an adverse prognosis; the downregulation may increase chemosensitivity |
|
| DNA damage [90] | Carcinogen-DNA adducts | Increased formation of aromatic hydrocarbon-DNA adducts and upregulation of the cytochrome P450 1A1 enzyme that metabolizes polycyclic aromatic hydrocarbons | This effect may contribute to an increased susceptibility to additional genetic damage |
|
| Increased intracellular ROS [105] | Altered signalling. DNA damage? | AML1-ETO causes increased intracellular levels of reactive oxygen species (ROS) in Drosophila | ROS are important for induction of the AML1-ETO associated phenotype and may also increase the risk of additional genetic abnormalities |
|
| Increased mutation frequency [91] | | Predisposition to leukemia progression | Predisposed for additional genetic effects that are required for leukemogenesis. |
|
| Cytokine-mediated growth regulation |
|
| IL3 [76] | Hematopoietic growth factor | Decreased gene expression | Decreased growth factor-dependent proliferation |
|
| M-CSF receptor [92] | Growth factor | M-CSF is a growth-enhancing hematopoietic growth factor | Increased cytokine-dependent AML cell proliferation |
|
| G-CSF receptor [93] | Growth factor | G-CSF is a growth-enhancing hematopoietic growth factor | Increased cytokine-dependent AML cell proliferation |
|
| BCL2 [94] | Antiapoptotic signaling | Upregulation by the AML1-ETO fusion protein | Increased antiapoptotic signaling |
|
| C/EBPε [92, 93] | Transcriptional regulator | Induction of G-CSF receptor expression; upregulation of the myeloid-specific promoter for the M-CSF receptor | Increased growth factor receptor expression and thereby increased cytokine-dependent proliferation by t(8;21) cells |
|
| NF1 [95] | Tumor suppressor | Decreased expression of the Neurofibromatosis1 (NF1) tumor suppressor | Decreased protein levels are associated with increased response of primary AML cells to GM-CSF |
|
| Tyrosine receptor kinase A [96] | A part of the nerve growth factor receptor (NGF) | Upregulation of this growth factor both at the mRNA and protein level | NGF is released by bone marrow stromal cells; in addition, AML1-ETO expressing cells show increased proliferation in response to growth factors |
|
| Cell-cycle regulation |
|
| p21 [97] | Negative cell-cycle regulator | Increased mRNA and protein levels of p21 | p21 is a cell-cycle inhibitor, this effect may contribute to the absence of leukemogenesis in the presence of t(8;21) alone |
|
| p27kip [98] | Negative cell-cycle regulator | Increased expression caused by either a direct effect of the fusion protein or by Cx43 | Cell-cycle inhibition |
|
| SSX21P [99] | Cell-cycle regulation? | Low expression of this molecule is associated with low expression of CDC20; possibly causing attenuation of the spindle checkpoint | Altered cell-cycle regulation, increased risk of aneuploidy? |
|
| Disrupted spindle checkpoint [100] | Aneuploidy | Disruption of the spindle checkpoint during cell-cycle progression | Increased risk of aneuploidy. |
|
| Regulation of apoptosis and stress responses |
|
| Annexin A1 [101] | Proapoptotic, antiproliferative | Downregulated at the gene expression level by the fusion protein | The molecule has proapoptotic and antiproliferative effects; these functions are thus inhibited |
|
| Connexin 43 (Cx43) [98, 102] | Gap junction component | Increased expression of Connexin 43 in cells with t(8;21), possibly both a direct and an indirect effect mediated via c-Jun | Cx43 often inhibits cell proliferation both through gap junction dependent and independent mechanisms; this effect may contribute to the lack of leukemogenesis by the full-length fusion protein |
|
| p53 [91] | Tumor suppressor | Activation of the p53 pathway | Possibly increased chemosensitivity and thereby contribution to the good prognosis of these patients |
|
| TXNIP [103] | Part of stress responses | Involved in reactive oxygen stress responses, AML cells with t(8;21) have increased protein levels of this molecule. The mechanism is not known | High levels inhibit the proliferation of myeloid progenitor cells; this may contribute to the good prognosis of these patients |
|
