Recently, it was reported that AML1-ETO induces self-renewal by the induction of C/D box snoRNA/RNPs, whereas another study defined FOXO1 as a critical regulator of the self-renewal program in AML1-ETO preleukemia cells. Over the last years it has become clear that the AML1-ETO oncofusion protein can also activate transcription by a mechanism involving p300 interactions. AML1-ETO was defined as a transcriptional repressor, although this does not represent all its biological functions. AML1-ETO consists of the DNA-binding domain (RUNT) of AML1 and four conserved domains of ETO. Eight-twenty-one (ETO) functions as a corepressor by recruiting the NCoR/SMRT/HDAC complexes. ĪML1 (RUNX1) functions as a DNA-binding transcription factor that is essential for fetal and adult hematopoiesis, and forms a complex with the core-binding factor β (CBFβ). This oncogenic cooperation results in enhanced self-renewal and differentiation arrest in hematopoietic progenitor and myelomonocytic cells.
In humans, t(8 21) AMLs are characterized by cooperating genetic aberrations, such as mutations of growth factor receptors, proto-oncogenes, and transcription factors such as stem cell factor receptor (c-Kit), FMS-related tyrosine kinase (FLT3), NRAS, PU.1 and AML1. In mice, secondary mutations are required to develop a full-fledged leukemia in the presence of intact AML1-ETO protein, although it was found that expression of a truncated AML1-ETO9a protein can give rise to full-blown leukemias. The most common chromosomal translocation in AML (10% of total AML) is t(8 21), which generates the AML1-ETO oncofusion protein and is mostly associated with a favorable prognosis The t(8 21) translocation is considered to be the initiating (driver) hit for further AML development and can sometimes already be observed in utero. Acute myeloid leukemia (AML) is an aggressive heterogeneous disease that is characterized by chromosomal translocations, insertions/deletions and point mutations.
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