AML1-ETO contra PU.1: another way to block myeloid differentiation

Acute myeloid leukemia (AML) is characterized by the outgrowth of immature myeloid cells often caused by specific chromosome translocations, such as t(8;21), which generates the AML1-ETO fusion protein. Previously, this protein has been shown to inhibit myeloid cell differentiation by 2 different mechanisms. As if this was not enough, a new study now indicates that there is yet another way to accomplish this.

AML1-ETO contains the N-terminal part of AML-1 (Runx-1), including the DNA binding domain. Together with CBFβ, AML-1 forms the core binding factor (CBF). CBF in turn is thought to recruit lineage-restricted transcription factors, such as C/EBPα, PU.1, and Ets-1, which regulate the expression of a variety of myeloid and T-cell–specific genes. Knock-in studies suggested that AML1-ETO acts as a dominant- negative version of CBF by displacing AML-1 from CBFβ, associating with corepressors and inhibiting critical target genes. Subsequent studies showed that AML1-ETO can also bind directly to the master myeloid regulator C/EBPα, thereby interrupting its autoregulation and inhibiting neutrophil differentiation.

The paper of Vangala and colleagues (page 270) now indicates that AML1-ETO can inactivate PU.1, another master regulator of myeloid gene expression. Although, as with C/EBPα, this again involves direct protein-protein interactions, the mechanism appears to be quite different since in this case it involves the displacement of the coactivator c-Jun from PU.1. Consequently, PU.1 no longer efficiently transactivates genes, although it can still bind to DNA. At least in vitro AML1-ETO, therefore, seems to silence target genes by a triple whammy (for example, the promoter of the CSF1-R gene is regulated by all 3 factors: AML-1, C/EBP, and PU.1). The findings reinforce the notion that for AML to develop, the activity of C/EBPα and PU.1 must be curbed by either mutations (as suggested by earlier work from Dr Tenen's lab [Pabst et al, Nature Med. 2001;7:444-451; Mueller et al, Blood. 2002. In press.]) or by antagonistic protein interactions.