Blood, 1 January 2003, Vol. 101, No. 1, pp. 2-2
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 CBF
, AML-1 forms the core binding
factor (CBF). CBF in turn is thought to recruit lineage-restricted
transcription factors, such as C/EBP
, 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 CBF, associating
with corepressors and inhibiting critical target genes. Subsequent
studies showed that AML1-ETO can also bind directly to the master
myeloid regulator C/EBP, 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/EBP, 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/EBP
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.
Thomas Graf
Albert Einstein College, College of Medicine
