The leukemia-associated RUNX1/ETO oncoprotein confers a mutator phenotype

t(8;21) is a frequent chromosomal translocation in acute myeloid leukemia (AML) and is also reported in lymphoid and biphenotypic acute leukemia. 1 , 2 t(8;21) fuses the RUNX1 gene ( AML1 ) on chromosome 21 to the ETO gene ( RUNX1T1 ) on chromosome 8, encoding the RUNX1/ETO chimeric transcription factor that represses expression of RUNX1 target genes, promoting self-renewal and blocking myeloid differentiation. 3 , 4 , 5 , 6 t(8;21) is insufficient for leukemogenesis and additional co-operating mutations are required for transformation, 7 including point mutations that activate and/or over express c-KIT. 8 The mechanisms driving the acquisition of co-operating mutations remain unclear, although there is evidence that initiating lesions such as RUNX1/ETO may promote mutagenesis. 9 , 10 For example, ectopic expression of RUNX1/ETO downregulates several DNA-repair proteins (BRCA2, OGG1 and ATM) and increases the level of phosphorylated TP53 and γH2AX, indicating elevated DNA damage and a possible pro-mutagenic phenotype. 10 , 11