A new inducible model for t(8;21) AML

Faithful and tractable mouse models for t(8;21)‐associated human acute myeloid leukaemia (AML) have been difficult to develop, limiting insight into the malignancy associated with this frequent chromosomal translocation. In this issue of EMBO Molecular Medicine , Cabezas‐Wallscheid et al. bring us a step closer to this goal with an improved Tet‐inducible mouse model of t(8;21)‐associated AML (Cabezas‐Wallscheid et al, 2013).The t(8;21) is found in approximately 10% of human AML and encodes for the leukaemia fusion protein AML1‐ETO (RUNX1‐RUNX1T1) (Miyoshi et al, 1993). The translocation results in a fusion protein comprised of the amino‐terminal part of RUNX1, including the conserved RUNT domain that is critical for function, and nearly the entire coding region of the ETO (RUNX1T1) protein. RUNX1 forms a heterodimeric transcription factor complex with the CBFβ protein. This complex is known as core binding factor (CBF), and both the RUNX1 gene on chromosome 21 and the CBFβ gene on chromosome 16 are involved in chromosomal translocations in 15–20% of human AML. CBF is a master regulator of haematopoiesis and knockout of either RUNX1 or CBFβ results in embryonic lethality due to failure of definitive haematopoiesis (Chuang et al, 2013). The ETO protein is a transcriptional repressor that associates with nuclear co‐repressor proteins and histone deacetylase activity. Although the molecular mechanisms through which AML1‐ETO exerts its effects are unclear, it is likely that the strong repressor function contributed by ETO is critical. Repression of numerous genes involved in haematopoietic differentiation, including CEBPA and SPI1 (PU.1), likely plays an important role in the functional outcome upon expression of AML1‐ETO. However, it is clear from various studies that AML1‐ETO is not solely functioning as a strong transcriptional repressor of CBF activity. Many genes are directly up‐regulated by AML1‐ETO, and the molecular mechanisms involved in these processes are the subject of …